this thesis is dedicated to the memory of william
TRANSCRIPT
This thesis is dedicated to the memory of
William Cruickshanks and Robert Rogers, my grandfathers.
Studies on the Synthesis and Heterocyclisation Reactions of
Aryl and Hetaryl Isocyanide Dihalides.
by
Mhairi Hay B.Sc.
Thesis presented for the degree of
Doctor of Philosophy
University of Edinburgh
1999
Declaration
I declare that this thesis is my own composition, that the work of which it is a record
has been carried out by myself and that it has not been submitted in any previous
application for a higher degree.
The thesis describes the results of research carried out in the Department of
Chemistry, University of Edinburgh, under the supervision of Dr. G. Tennant between
October 1993 and September 1996.
Acknowledgements.
I would like to thank Dr. G. Tennant for his supervision and encouragement during
the course of my research.
I would like to thank the University of Edinburgh for the provision of my funding,
laboratory and library facilities.
I would also like to acknowledge the help and expertise of the technical staff of the
Department of Chemistry, University of Edinburgh, notably Mr. J. Millar and Mr. W.
Kerr for the measurement of n.m.r. spectra, Mrs. E. McDougall for the determination
of microanalysis and Mr. A. T. Taylor for the mass spectra recorded in this thesis.
Postgraduate Lecture Courses Attended
between October 1993 and April 1996.
"Current Topics in Organic Chemistry"
Various Lecturers (University of Edinburgh)
"Aspects and Applications of NMR spectroscopy"
Drs. I. Sadler and P. Barlow (University of Edinburgh)
"Discovery of Agrochemicals"
Drs. G. Godfrey and T. Perrier (Zeneca Agrochemicals)
"Fine Chemicals"
Prof. MKillop (University of East Anglia)
"Peroxygens"
Solvay Interox
"Industrial Biocatalysts"
Drs. J. Sime and L. Powell (SmithKline Beechams)
Department Seminars and Colloquia.
"Industrial Chemistry - From research to development"
Zeneca
"Recent Developments in the Discovery of CCK 8 Antagonists"
Merck, Sharp and Dobme.
"Industrial Chemistry - Processing High Density Polyethylene, and Industrial
Separation Processes."
Drs. B. Morton and D. Glass.
Abstract.
The subject matter of this thesis is concerned with investigations of novel
heterocyclisation reactions of isocyanide dihalide derivatives and extends previous
studies conducted at Edinburgh on such processes which provide general routes to
tricyclic heteropines. The description of the results obtained in these studies is
preceded in chapter 1 by a survey of known reactions of such compounds and their
synthesis.
Isocyanide dihalides have the ability to undergo intramolecular Lewis acid promoted
cydlisation reactions. Chapter 2 describes investigations into the synthesis of various
dihaloisocyanophenylamine derivatives and attempts to achieve their subsequent
Lewis acid catalysed reactions to dibenzo [b,f]- 1 ,4-diazepine derivatives.
Unfortunately in the majority of cases studied the Lewis acid promoted cydlisation
reactions were found to be unsuccessful. When successful Lewis acid catalysed
cyclisation occurred nucleophilic displacement reactions of these halogenated
products were also briefly investigated.
Chapter 3 expands on the general synthetic route developed in chapter 2 and describes
the synthesis of various isocyanide dihalide derivatives, all of which had the potential
to undergo Lewis acid catalysed cyclisation to polycycic heteropine and heterocine
derivatives including benzonaphthoxazepines, pyridonaphthoxazepines and
dibenzoxazocines. In the case of naphthyloxyphenylisocyanidedihalides, Lewis acid
catalysed cydlisation led to benzonaphthoxazepine derivatives but was complicated
by halogenation of the naphthalene ring. Attempts were made to investigate the
source of the halogenation of the naphthalene ring in order to simplify the Lewis acid
catalysed cyclisation reactions. The Lewis acid catalysed cyclisation of
naphthyloxypyridylisocyanidedihalides led to pyridonaphthoxazepine derivatives,
which were also complicated by halogenation of the naphthalene ring.
Preface
Isocyamde dibalide derivatives are currently of interest because of their utility as
intermediates in the synthesis of heterocyclic compounds with potentially important
chemical and biological properties.
The use of a Fnedel - Crafts type cyclisation reaction of isocyanide dihalides was
previously reported at Edinburgh. This interesting cyclisation reaction prompted
investigations into the synthesis of novel or otherwise difficult to obtain heterocycles.
The results of these investigations are reported in the following thesis and, by way of
introduction, are preceded by a survey of known literature methods for the synthesis
of isocyanide dihalides and their conversion into heterocyclic compounds.
Contents
CHAPTER ONE INTRODUCTION: A Survey of the
1
Biological Properties and Methods for the
Synthesis of Tricycle Heteropines
CHAPTER TWO Investigations of Lewis Acid Catalysed
12
Isocyanide Dihalide Reactions leading to
Dibenzo[b,fl-1,4-diazepines and Related
Fused Structures
CHAPTER THREE Studies of Synthetic Routes to Polycydic
78
Heteropine and Heterocine Derivatives based
on Isocyanide Dihalide Cyclisation Reactions
Bibliography 210
Chapter One.
A Survey of the Biological Properties and
Methods for the Synthesis of Tricyclic Heteropines.
2
1.1 Introduction.
This chapter is subdivided into two sections. In the first section the biological activity
of tricyclic heteropines is briefly surveyed with particular emphasis on their potential
use as neuroleptic agents for the understanding and treatment of Alzheimer's disease
and schizophrenia. The second provides an overview of currently available methods
for the synthesis of tricyclic heteropines.
1.2 Biological Pronerties of Tricyclic Heteropines.
Tricyclic heteropines are of potential importance as agents for the treatment of a wide
variety of conditions ranging from Alzheimer's disease 1 and schizophrenia on the
one hand to inflammatory conditions on the other.' In particular a substantial number
of investigations have been reported 4 on the use of tricyclic heteropine derivatives as
neuroleptic agents for the treatment of schizophrenia.
Schizophrenia is a severely debilitating mental condition which affects approximately
one percent of the world population. Although disorders resembling schizophrenia
have been reported since the twelfth century B.C. most of what is understood about
the disease has its origins in more modern times. 5 In 1911, Beuler, a Swiss psychiatrist
was the first to use the term schizophrenia to describe the various elements of the
illness. Schizophrenia is a psychiatric disease of the type clased as psychoses, as
opposed to neuroses. 6 Neurotic patients show exaggerated response to the normal
(e.g. anxiety, depression) but are aware of their illness. Psychotic patients on the other
hand live in a world of their own which has little basis on reality. Schizophrenia shows
a progressive development of disturbed thinking, altered mood and unusual
interpersonal behaviour. The main symptoms of the disease can be categorised into
two groups. The initial, positive symptoms, include delusions, hallucinations
(auditory) and illogical trains of thought. In some cases disturbed thinking can lead to
paranoia. 7 The negative symptoms are apathy, lack of motivation, loss of emotional
response, loss of social interactions and dementia. The positive symptoms are believed
to result from a neurological abnormality while the negative symptoms originate in the
shrinkage of the left hemisphere of the brain, as revealed by computerised
tomography. It is therefore feasible that the biochemical abnormality that causes the
positive symptoms leads to gradual degeneration of neurons which in turn results in
brain shrinkage.
In recent years 8 three main theories on the biochemical origins of schizophrenia have
been proposed. The theory for the likely cause of schizophrenia currently attracting
most interest is the dopamine hypothesis. 9 This theory is relatively simple and is
based on the postulate that if cerebral dopaminergic activity is enhanced,
schizophrenia in a patient will get worse, whilst if dopaminergic activity is reduced
then the symptoms of schizophrenia will also be reduced.
Dppamine is the most common neurotransmitter in the brain. 10 However different
dopamine receptors are found in different areas of the brain (Figure 1). The D2
Frontal cortex
Caudate nucleus and putamen (striatum)
L - - - - Nucleus accumbens : (ventral stnatum)
Tuberoinfundibular DA system
Nigrostriatal DA system
Amygdala
I Ventral Mesoflmbic and tegmental mesocortical area DA system
Substantia nigra
4
receptor is localised in the nigrostriatial pathway (Figure 1) and has lower levels in
various cortical areas. The nigrostriatial pathway is associated with the control of
movement. The D3 and D4 receptors are found only in low levels in the striatum
(Figure 1) but are found in high concentration in the dopaminergic cortical and limbic
areas. (Figure 1).
Drugs (Scheme 1) such as amphetamine (1) cause dopamine release in the brain and
produce a syndrome which is indistinguishable from the positive symptoms of
schizophrenia. Potent D2 - receptor agonists, for example (Scheme 1) bromocriptine
(2) make the symptoms of schizophrenic patients worse and drugs which are
dopamine D2 receptor antagonists are effective in controlling the positive symptoms
of schizophrenia. This has led to the development of several dopamine D2 - receptor
antagonists as drugs to treat schizophrenia. 8
One group (Scheme 1) the so called typical neuroleptics such as chlorpromazine (3)
and more recently halopendol (4), though successful in treating the positive symptoms
of schizophrenia are unable to eradicate the negative symptoms of the illness.
Moreover, as well as being antipsychotic agents chlorpromazine (3) and haloperidol
(4) have a variety of side - effects. ' These include sedation, hypotension, blurred
vision, urinary retention and most importantly the tendency to induce extra -
pyramidal symptoms (muscle rigidity, loss of mobility, tremor, and involuntary
movements) which resemble those associated with Parkinson's disease The
Me (L
NH2
I II
(1)
Me e
N le
0 NyL o
M
:3
(2)
as:o (CH 2 ) 3 NMe2
(3)
CI
(4)
Me It
0 )ND
(5)
Scheme 1
5
Parkinsonism - like side - effects only appear after taking the drugs for years but these
side - effects continue even after use of the drug is discontinued. The typical
neuroleptics have a high affinity for the D 2 receptor. Since the D 2 receptor is the
dominant type of dopamine receptor in the striatum (Figure 1) , which plays an
important role in the control of motor behaviour it is believed that it is the blockage of
these receptors that causes the unwanted extra - pyramidal side - effects. Since the
D3 and D4 receptors are not found in the striatum in high levels their blockage by a
selective drug should treat the symptoms of schizophrenia without the extra -
pyramidal side - effects.
The tricyclic heteropine (Scheme 1) clozapine (5) unlike "typical" neuroleptics is a
relatively weak D2 receptor antagonist. It does however have a high affinity for the D 4
receptor. 12 Clozapine is therefore referred to as an "atypical" neuroleptic because its
pharmacological profile differs from that of the typical neuroleptics. Thus it not only
suppresses the positive symptoms of schizophrenia but also the negative symptoms.
Also clozapine does not cause extra - pyramidal side - effects. Unfortunately,
however, when clozapine was first introduced as an antipsychotic agent in the 1970's
it was found to cause agranulocytosis, 13 a potentially fatal disorder of the white
blood cells. Because of this dangerous side - effect clozapine had to be withdrawn as
an otherwise useful agent for the treatment of schizophrenia. Recently clozapine has
been reintroduced in conjunction with blood monitoring in several countries for the
treatment of patients whose schizophrenia has failed to respond to other protocols.
Because of its exceptional antipsychotic activity clozapine has stimulated the quest for
safer alternatives, particularly tricyclic heteropine derivatives, for the treatment of
schizophrenia. To date this quest has been unsuccessful.
Another area where tricyclic heteropines have a part to play as medicinal agents is in
the treatment of Alzheimer's disease. At present there is no cure for this disease which
is the most common cause of mental deterioration in the elderly. Alzheimer's disease
was first recognised in 1907 by the German neurologist Alois Alzheimer. 14 There has
been an increased awareness of Alzheimer's disease in recent years due to the
increased proportion of elderly people in the population. This continuing increase in
the number of elderly people will lead to a proportionate increase in the number of
people suffering from Alzheimer's disease.
The early symptoms of Alzheimer's disease are short term memory loss and the
inability to recall events. These symptoms are similar to problems associated with the
normal ageing process. As the disease develops all memory is lost, the individual's
behaviour changes and they become unable to perform normal daily tasks. The
individual then becomes bedridden and death normally occurs from conditions related
to this. However it is not until after death, when a post mortem is carried out, that a
definite diagnosis of Alzheimer's disease can be made. Alzheimer's disease is
associated with a general shrinkage of brain tissue. 8 Closer exan,iipation, by
7
microscope, shows a high density of abnormal deposits amongst brain cells. These
deposits, which are called neurofibrillary tangles and neuritic plaques, are found in
areas of the brain involved with higher intellectual function and memory.
Neurofibrillary tangles are bundles of twisted protein filaments, while neuritic plaques
are structures of cellular debris around a central core of an amyloid (a protein).
Neurochemical studies have shown that in the hippocampus and cerebal cortex of the
brains of patients suffering from Alzheimer's disease the level of the enzyme choline
acetyltransferase is reduced by up to 90%. 15 The enzyme, choline acetyltransferase, is
involved in the synthesis of acetylcholine, which is a neurotransmitter found in areas
of the brain connected with memory. Reduction in levels of choline acetyltransferase
leads to a reduction of this important neurotransmitter. This leads to the cholinergic
hypothesis which postulates that if Alzheimer's disease is due to a lack of
acetylcholine then a drug that restores the level of acetylcholine should be useful in
the treatment of the disease. One possible way of accomplishing this is to use a
cholinergic receptor agonist. Cholinergic receptors are muscarinic receptors of which
there are two types, M 1 and M2 . M2 receptors are found in the heart and gut and in
areas of the brain regulating blood pressure. M 1 receptors are found mainly in the
central nervous system, in the cortex and hippocampus. Because of their location M 1
receptors are believed to be connected to an individual's ability to think. A suitable
cholinergic receptor agonist for the treatment of Alzheimer's disease should therefore
ideally be selective for the M 1 receptors to prevent unwanted side - effects from the
concomitant stimulation of the M2 receptors. Compounds investigated 16 so far
0 Me
C-. A 0 Me
N 0
I Me. H
(6) (7)
H 0 N-1
0
0 M
Me o
CL N(CH3)3 CN (8)
Me
(9)
Scheme 2
(Scheme 2) include arecoline (6), pilocarpine (7) and bethanechol (8). Unfortunately
all of those compounds had limitations including short half - life and lack of specificity
for the central nervous system or limited ability to cross the blood - brain barrier.
None of the drugs (6) - (8) was of significant benefit to patients.
One compound (Scheme 2) which is selective for M 1 receptors is the tricyclic
heteropine pirenzepine (9). However pirenzepine (9) cannot cross the blood - brain
barrier and therefore has no central nervous system activity. It may however be
possible to synthesise derivatives of pirenzepine's tricyclic heteropine structure which
have the required M 1 receptor selectivity as well as the ability to enter the brain. Such
compounds might then prove to be suitable therapeutic agents for Alzheimer's
disease.
1.2 Methods for the Synthesis of Nonbridgehead - fused Tricyclic Heteropines.
Currently there are no generally applicable synthetic routes to tricyclic heteropines.
This lack of synthetic methodology is a hindrance to the development of research into
the biological activity of these compounds. If the synthetic chemist was able to modify
tricyclic heteropines in a flexible way it would be easier to provide structurally
variable compounds for screening. The most useful routes to tricyclic heteropines
leave the closure of the seven membered ring to the end. The vast majority of
syntheses rely on one or other of three general approaches.
H 0
71) (I)
OH CI
R ****.CC N H 2
OH
(10)
c( +
1 Cl N
(11)
(12)
H 0
(13) (R=H, CH3, Cl)
H 0 NH2 CO2H
R"
R' x R2
(14)
(15)
X R' 0 OCH3 H S H NH2
THF, reflux. NaOEt, DMF, reflux. 180°C.
Scheme 3
One approach (Scheme 3) involves an intramolecular nucleophilic aromatic
substitution reaction as the final ring - closure step. The initial amide link is formed by
the condensation of an aromatic amine (10) with a suitable carbonyl compound [e.g.
an acid chloride (11)] then ring closure is achieved by intramolecular nucleophilic
displacement of the chioro substituentin the intermediate (12) by the hydroxyl
function to give the tricyclic heteropine (13). This type of tricyclic heteropine
synthesis has been successfully demonstrated using amides and amines. ' 7
A second general approach to tricyclic heteropines (Scheme 3) involves initial
formation of the heteroatom bridge -between two aromatic rings then ring closure by a
condensation reaction between an amino group and an appropriate carbonyl
substituent. This strategy has -been used for the construction of various tricyclic
heteropine ring systems, for example dibenzoxazepines (15a) from aminodiphenyl -
ether carboxylic acids (14a) in high yield (92%).18 Ring closure of this type involves
temperatures of around 200 °C. It is, however, possible to use the same strategy, at
lower temperature, using phosphoric acid as a catalyst as in the synthesis of
dibenzothiazepinones [(14 b) -> (15 b)]. 19
The third common route to tricyclic heteropines involves an intramolecular
electrophilic aromatic (Friedel Crafts) substitution reaction as the final ring - closure
step.. This strategy (Scheme 4) is illustrated by the synthesis of the parent
dibenzoxazepine (21).20 The heteroatom bridge is formed by the reaction of
NO2
C NO2
ccl OH 0 + II I 0) ir
(16) (17) (18)
I(ii)
NHCHO NH
(iii)
(20) (19)
cco (21)
Nall, Cu, DMF, 150 - 160'C. H2, Pd - C, EtOH, room temp. HCO2H, reflux. POC13 , polyphosphoric acid, 100°C.
Scheme 4
R r R
NH N-='
Lx
(22) (23)
(X0, S,NMe,CH2) (R = H, Me)
0 NJ
N=C=O NH
(24) (25)
-4) CH 3
0 N
c(To (26)
x a;O b; S
Polyphosphoric acid, 150°C. N-methylpiperazine, benzene, reflux. POC13, reflux.
Scheme 5
10
2-chloronitrobenzene (16) with phenol (17) to give the nitrophenol (18). Reduction of
the nitrophenol (18) then reaction of the amine (19) with formic acid gives the
formamide (20). The formamide (20) is then ring - closed with phosphoryl chloride to
form the dibenzoxazepine (21). This strategy has been extended 21 (Scheme 5) to the
polyphosphoric acid catalysed cyclisation of appropriately functionalised amides [(22)
-~ (23). This type of cyclisation has also been used successfully in the synthesis of
dibenzothiazepines. 22 A further extension of this type of cyclisation to form tricyclic
heteropines (Scheme 5) involves the use of ureas (25 a - b) in the ring closure step.
The ureas are formed from the corresponding isocyanates (24 a - b) and give
dibenzoxazepine (26a) and dibenzothiazepine (26b).
Previous studies at Edinburgh 23 have shown that isocyanide dihalides can be
successfully used in Friedel - Crafts like cyclisation reactions (Scheme 6). The
isocyanides (29a - c) were obtained by the dehydration of the formamides (28a - c),
which themselves were obtained by formylation of the readily accessible amines (27a -
c). The isocyanide dibromides (30a - c) are obtained from the isocyanides (29a - c) by
the reaction with molecular bromine. In turn heating the isocyanide dibromides (30a -
c) with aluminium tribromide gave the dibenzoheteropines (31 a - c) providing a novel
general route to tricyclic heteropines. To date only a limited number of compounds
have been studied, as part of this thesis other compounds have been studied in an
attempt to discover the range of compounds that can be synthesised in this way.
H
NH N—CHO
c o_(i) (27) (28)
(ii)
Br IF + -
N Br NC
(30) (29)
Br
c 4o (31)
x a;O
S NSO2Ph
HCO2H, reflux. Ph3P, CCU, Et3N, C1(CH2)2C1, 60°C. Br2, CH202, -10°C. AIBr3, CH202, reflux.
Scheme 6
11
There are many other synthetic routes to tricyclic heteropine derivatives but they all
suffer drawbacks: most important of these are harsh reaction conditions, especially in
the ring closure step where high temperature and polyphosphoric acid are used. There
is also limited availability of the required starting materials thus limiting the range of
available structures. By developing the cyclisation of isocyanide dihalides using the
conditions previously described (Scheme 6). It is hoped that this will lead to a general
cyclisation route for tricyclic heteropines and their derivatives thus leading to the
synthesis of many new tricyclic heteropines to establish a better understanding of their
biological activity.
12
Chapter Two.
Investigations of Lewis Acid Catalysed Isocyanide Dihalide Reactions
leading to
Dibenzolb.fl-1.4-diazepineS and Releated Fused Structures
Me CN
101
CL~jj
(5)
Scheme 7
N ci{( iTh
Ts
(32)
Br
Ts
(i) cl
(33)
Me
0 N
cl
AN) Ts
Br
cçp-' --1 Ts
(35) \ (34) (iv) or (v)\ Me
0 N /
cl
AN)
(5)
Br2, CH202, -10°C. AIBr3, CH2C12, room temp. NaH, N-methylpiperazine, DME, reflux. Na, NH3 (1), -33°C. 30% w/v HBr-AcOH, reflux.
Scheme 8
13
Investigations of Lewis Acid Catalysed Isocyanide Dihalide Reactions leading to
Dibenzolb1I-1,4-diazepines and Related Fused Structures
2.1 Introduction
Clozapine (5) (Scheme 7) is used in the treatment of schizophrenia. Clozapine (5),
unlike other drugs used in the treatment of the disease, does not cause extra -
pyramidal side - effects and therefore is medically very important. Unfortunately due
to unwanted, potentially fatal, side - effects clozapine (5) must be used under strictly
controlled conditions. Because of the beneficial action of clozapine other structurally
similar compounds lacking unpleasant side - effects are of interest as drugs for the
treatment of schizophrenia.
Clozapine (5) is a dibenzo [b,f]-1,4-diazepine derivative containing a chloro group at
the 8-position, a 4-N-methylpiperazin- 1 -yl group at the 11-position and lacking a
substituent at N-S. General access to clozapine analogues therefore requires a flexible
general route to 5-N-unsubstituted dibenzo [b,f]- 1 ,4-diazepine derivatives. Previously,
at Edinburgh University 2' research into a general synthetic route to 5-N-unsubstituted
dibenzo [b,f] - 1,4-diazepines had been attempted. Overall the route had been
relatively successful the only set back being the inability to remove the protecting
group from the 5-N-position. One example (Scheme 8) of this general route is shown
from the isocyanide derivative (32). The key step in this synthesis was the Friedel -
Crafts type cydlisation of the isocyanide dibromide derivative (33) to form the 5-N-
R—I + -
MCN [RNC—Ml] R—N1-
C
(36)
(37)
(38)
(39)
(R = alkyl; M = Ag or Cu)
Scheme 9
C H Cl 3
Cl R—NH 2 + :CCI2 10. R-N--C CI
H1 R—NC,2
(;Cl
4. - R—NEC
(39)
Scheme 10
HO ' H Cl R—N—C—H
C,
14
substituted dibenzodiazepine derivative (34). The bromo group at the 11-position in
the latter allows for a nucleophilic displacement reaction at this site. Such
displacement provides the potential for the synthesis of a variety of 11-substituted, 5-
N-substituted analogues of clozapine (5), and after removal of the 5-N-substituent, of
clozapine itself Unfortunately, in the previous studies 23 removal of the protecting
group from the 5-N-position was unsuccessful and thus further research into finding a
suitable protecting group was required.
In the above synthesis the route to the isocyanide dibromide derivative (33) and thus
the key cyclisation step, was via the isocyanide derivative (32). Until recently there
was no efficient general route to isocyanides. Since isocyanide dihalides are generally
synthesised from the corresponding isocyanide exploration of isocyanide dihalide
chemistry has been limited. Isocyanides were first reported over one hundred years
ago by Gautier 24 and Hofmann 25 The first isocyanides were prepared (Scheme 9) by
the reaction of alkyl iodides (36) with silver cyanide (37a) or copper cyanide (37b)
alkylation occurring preferentially at nitrogen rather than at carbon, through the
intermediacy of an isocyanide metal iodide complex (38). This isocyanide synthesis
however gives low yields. 26 At about the same time as Gautier reported his
isocyanide synthesis, Hofmann described the carbylamine reaction. This involves
reaction of a primary amine with chloroform in the presence of a strong base (e.g.
sodium hydroxide) and is believed to follow the mechanism shown in Scheme 10. As
an extension of the carbylamine transformation it was proposed (Scheme 11) that the
H
R—N—CHO -H20
R—NC
(40)
(39)
H + - I
Ph3P + Cd4 so Ph3P—CCI3 Cl + R—N—CHO
Et3
(40) +
CHCI3 + RN=C + - R—NC + Ph 3 P=O + Et3 NHCI
(\5_PPh3CI
+
R—NC 4
R—NC:
(41a)
(41 b)
Scheme 11
15
dehydration of secondary formaniides (40) could provide an alternative general route
to isocyanides (39). In practice various reagents 27 (e.g. cyanuric chloride,
benzensulfonylchloride, phosphorus trichioride, phosphorus oxychloride, thionyl
chloride) were indeed found to have the ability to dehydrate secondary formamides in
the presence of bases (e.g. trialkylamines, pyridine) to give isocyanides in good yield.
More recently Ugi 28 has shown that reaction with phosgene followed by triethylamine
provides one of the best methods for the conversion of secondary formaniides into
isocyanides. One reagent combination which appears to be suitable for the synthesis
of many isocyanides from the corresponding primary formamides is phosphoryl
chloride and diisopropylethylamine. This method not only eliminates the need to use
the highly toxic phosgene but tends to give increased yields of isocyanides.
Another reagent combination (Scheme 11) which is particularly appropriate for the
synthesis of aliphatic and aromatic formamides is triphenyiphosphine and carbon
tetrachloride in the presence of triethylamine. The mechanism for this isocyanide
synthesis is believed 29 to be as shown in Scheme 11.
The reactivity of the isocyano functional group is consistent with its electronic
structure (Scheme 11) which can be viewed as a resonance hybrid of two possible
canonical forms [(41a) -> (41b). The dominant structure is the dipolar form (41a),
the carbenic form (41b) making a lesser contribution. Because of its electronic
structure the reactivity of the isocyano group is dictated by the desire of the terminal
Hal (i) /
R—NC 10 R—N=C Hal
(39) (42)
C12, S02C12 , or Br. C12 or S0202 .
Scheme 12
4 (II) R—NCS
(43)
Hal Cl Br
16
carbon atom to regain the stable tetracovalent state. This means that isocyanides tend
to undergo electrophilic addition. Throughout the ensuing discussion the isocyanide
group will be formulated as the dipolar structure (41a).
Although the availability of an efficient general route to isocyanides was an important
factor in the studies pursued in this thesis the key synthetic intermediates were in fact
the derived isocyanide dihalides. Prior to the ready availability of isocyanides the only
route (Scheme 12) to isocyanide dichiorides (42a) had been the chlorination of
isothiocyanates (43)•3) With the current ready accessibility of isocyanides (39), simple
reaction of the latter with chlorine or bromine or other halogenating agents such as
suiphuryl chloride in a suitable solvent (e.g. dichloromethane) at room temperature or
below provides a simple general route to the corresponding isocyanide dichiorides
(42a) or dibromides (42b) usually in quantitative yield. In practice the conversion of
isocyanides (39) into isocyanide dichiorides (42a) is most conveniently accomplished
using suiphuryl chloride as the chlorinating agent thereby avoiding the use of gaseous
chlorine.
Iso cyanide dihalides are structurally similar to phosgene (C1 2C0) and it has been
found that their chemical reactivity is related. 31 The most commonly described
reactions of isocyanide dihalides involve the nucleophilic displacement of one or both
of the halogen atoms. Displacement reactions of this type can be accomplished
sequentially using two different nucleophilic reagents or both halogen atoms can be
17
displaced at the same time. Isocyanide dihalides have been used in the synthesis
(Scheme 13) of a wide variety of heterocycles through ring-closure reactions with
diverse nucleophilic reagents. 32
2.2 Studies on a New General Route to 5-N-unsubstituted Dibenzolb.fI-1.4-
diazepine Derivatives including Clozapine
As already described in Section 2.1 isocyanide dihalides have the potential to be used
as key intermediates in intramolecular Friedel - Crafts type cyclisation reactions to
form dibenzodiazepines. 23 In the present studies it was therefore decided to exploit
this novel type of heterocyclisation reaction in a new and potentially general synthesis
of 5-N-unsubstituted dibenzo[b,f]-1,4-diazepine derivatives including clozapine (5).
The proposed synthesis (Scheme 14 and 15) involved the initial formation of the
chloronitrobenzenamine derivative (46). This compound was prepared, in good yield,
as described in the literature by reaction of 2,5-dichloronitrobenzene (44) with
aniline (45) in the presence of sodium acetate. The chloronitrobenzenamine derivative
(46) reacted as expected with ethyl chloroformate in dimethylformamide at room
temperature in the presence of sodium hydride to give a good yield (78%) of a
product which analysed correctly and gave mass, 'Hn.m.r. and i.r. spectra in accord
with its formulation as the N-protected chloronitrobenzenamine derivative (47).
Reduction of the N-protected derivative (47) was first attempted using hydrogen in
the presence of Raney nickel catalyst in acetic acid at room temperature and
cl
CO2 Et
(50)
Hal /
NHal
CO2 Et
(51)
Hal
)N DCl CO2 Et
(52)
I I
0 /
I /
0 Me
NJ N-
CO2Et
(5)
(Hal = Cl or Br)
Scheme 15
co CO2Et
(53)
(54)
Iii N—CHO
N >O CO 2 Et
(56)
(iv) or (v)\
N"O
CO2 Et
(57)
C1CO2Et, NaH, DMF, room temp. H2, Pd-C, EtOH, room temp, atmos. pres. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp. C13COCO.00C13, Et3N, CH202, reflux.
Scheme 16
CO2 Et
(55)
18
atmospheric pressure to give the required primary amino derivative (48) in low yield
(45%). The amine (48) analysed correctly and showed spectroscopic properties
which fully support its assigned structure. The use of stannous chloride as a reducing
agent in tetrahydrofuran in the presence of aqueous hydrochloric acid improved the
yield of the amine (48) to 75%.
The attempted formylation of the amine (48) using formic acid under reflux afforded a
single product in poor yield (31%) whose accurate mass, 'Hn.m.r and i.r. spectra was
correct for the expected formaniide derivative (49). Attempts to improve the yield of
the formaniide (49) were unsuccessful.
Due to the limited success in obtaining the formamide derivative (49) and hence a lack
of material to proceed via the isocyanide (50) to the desired halogenated
dibenzodiazepine derivative (52) (Scheme 15) and thence clozapine (5) it was decided
to apply the synthetic strategy represented in Schemes 14 and 15 to the synthesis
(Scheme 16) of the simpler isocyanide (57) which it was hoped could be further
elaborated to N-unsubstituted dibenzodiazepine derivatives akin to clozapine (5).
Initially the N-ethoxycarbonyldiphenylaniine derivative (54) was synthesised by
reaction of commercially available 2-nitrodiphenylamine (53) with ethyl chloroformate
using the method described in the literature. 34,35 Catalytic reduction of the nitro
derivative (54) also proceeded in quantitative yield, as described in the literature, 34,35
to afford the amino derivative (55). Reaction of the amino derivative (55) with formic
CNQ
CO2Et
(57)
Br
N C Br
(i)
CO2Et
(58)
Br
cço CO2Et
(59)
N
cC 1ND CO2Et
(60)
Br2 , CH202, -78°C. AIBr3 , CH202 , - 10°C, room temp or reflux. NaOH, EtOH, reflux. piperidine, MeCN, reflux.
Scheme 17
i
iv)
v) (D 1ND CO2Et
(61)
19
acid under reflux afforded a product, in good yield (71%), which analysed correctly
and gave 'Hn.m.r., mass and i.r. spectra consistent with its formulation as the
formamide (56).
The next step in the strategy was the dehydration of the formaniide derivative (56) to
the isocyanide (57). The formamide (56) was therefore reacted with phosphor)'l
chloride in the presence of diisopropylethylamine in dichioromethane at room
temperature to give a good yield (74%) of the required N-ethoxycarbonyl, N-phenyl
2-isocyanobenzenamine (57). This previously undescribed compound analysed
correctly and showed mass, i.r. and 'Hn.m.r consistent with its assigned structure.
Having successfully obtained the isocyanide derivative (57) its conversion (Scheme
17) into the isocyanide dibromide (58) was next attempted. In practice reaction of the
isocyanide (5 7) with bromine in dichioromethane at -10°C gave a quantitative yield of
the required isocyanide dibromide derivative (58). Due to the unstable nature of other
isocyanide dibromides synthesised at Edinburgh 23 combustion analysis of the oily
iso cyanide dibromide (58) was not possible. However the high resolution mass
spectrum of the product was consistent with the isocyanide dibromide structure (58).
With the isocyanide dibromide (58) to hand its cyclisation to the
bromodibenzodiazepine (59) was next investigated. Reaction of the isocyanide
dibromide derivative (58) with aluminium tribromide in dichloromethane afforded a
20
product in excellent yield (88%) which gave accurate mass, 'Hn.m.r and i.r. spectra
consistent with that of the bromodibenzodiazepine derivative (59).
The presence of the potentially readily displaceable bromo - group in the
bromodibenzodiazepine (59) makes the latter a valuable intermediate for the synthesis
of a wide variety of clozapine analogues. In an initial attempt to evaluate the
reactivity of the bromo group towards nucleophilic displacement and also verify the
structure of the bromodibenzodiazepine derivative (59) its reaction with sodium
hydroxide in ethanol was attempted. However this reaction gave only a complex
mixture with no evidence for the formation of the expected lactam derivative (60).
An attempt was also made to displace the bromo - group in the dibenzodiazepine
derivative (59) with piperidine to obtain the piperidyl derivative (61). However the
reaction of the bromodibenzodiazepine derivative (59) with piperidine in acetonitrile
under reflux gave only a complex mixture with no evidence for the formation of the
compound (61).
The failure of the bromodibenzodiazepine (59) to undergo straightforward
nucleophilic displacement of the bromo group due to complicated side reactions
involving the ester substituent. It was therefore decided to synthesise (Scheme 18)
the N-methyl bromodibenzodiazepine derivative (67) in order to evaluate the
reactivity of the bromine atom in this compound, without the possible complicating
presence of the ester substituent.
NO2 NO2
(I)
H Me
(53) (62)
H
(ii)
N—CHO NH2
N'O c(o
Me Me
(64) (63)
(iv) or (v/ or2f
Br I
—C-
NC N- Br
- N I I
Me Me
Br
d N-
No
Me
(65)
(66)
(67)
MeSO4, NaH, DMF, room temp. SnC12 , HC1, THF, reflux. HCO2H, reflux. POC13, P?2NEt, CH202, room temp. C13CO.CO2CC13, Et3N, CH202, room temp. Ph3P, CCLI, Et3N, CH202, 60°C. Br2, CH202 , -78°C.
Scheme 18
21
The first step in this synthesis (Scheme 18) was the reaction of the commercially
available 2-nitrodiphenylamine (53) with dimethyl sulphate to give the known 34 ' 36 N-
methyl, N-phenyl 2-nitrobenzenaniine (62) in excellent yield (97%). The reduction of
the nitro compound (62) using stannous chloride in aqueous tetrahydrofuran in the
presence of hydrochloric acid as described by Bell34 gave the amino compound (63)
in good yield (84%). The amine (63) reacted as expected with formic acid under
reflux to give a reasonable yield (53%) of a product which analysed correctly and
gave i.r., 1Hn.m.r and mass spectra in accord with the previously undescribed
formamide derivative (64).
Reaction of the formamide derivative (64) with phosphoryl chloride in
dichioromethane at room temperature in the presence of diisopropylethylamine gave
the isocyanide (65) though only in moderate yield (47%). In an attempt to improve
the yield of the isocyanide derivative (65) the formamide (64) was reacted with
triphosgene 34 in 1 ,2-dichloroethane in the presence of triethylamine at room
temperature. Unfortunately this reaction gave only an intractable gum which showed
no evidence for the presence of the presence of the isocyanide (65). A further attempt
to obtain the isocyanide (65) was made by reacting the formamide (64) with
triphenylphosphine and carbon tetrachloride in 1 ,2-dichloroethane in the presence of
triethylamine. These conditions gave the isocyanide (65) in slightly improved yield
(64%).
22
Having successfully obtained the isocyanide derivative (65) its conversion into the
isocyanide dibromide (66) was next attempted. Unfortunately reaction of the
isocyanide (65) with bromine in dichioromethane at -78°C gave a complex mixture
which gave no identifiable material. It is not obvious why the isocyanide derivative
failed to afford the dibromide (66) particularly since the corresponding N-benzyl
derivative (65; phenyl for Me) affords the isocyanide dibromide (66; phenyl for Me)
cleanly and in essentially quantitative yield. 23 However in view of the difficulties
encountered in obtaining either of the isocyanide dibromide starting materials (58) and
it was decided to terminate these particular studies at this stage.
2.3 Investigations of Lewis Acid Catalysed Cyclisation Reactions of Fused
Diphenytamine Isocyanide Dihalides.
As a continuation of studies in section 2.2 it was decided to further exploit the
intramolecular Friedel - Crafts type cydlisation reactions of isocyanide dibromides. As
previously discussed a general route to diphenylamine isocyanide dibromides and their
Lewis acid catalysed cydlisation had been developed but unfortunately previous
studies had been unable to find a suitable protecting group of the resulting 5-N-
position of the dibenzodiazepine derivatives. As an alternative it was therefore
decided to exploit the potential 5-N-protection afforded by fused diphenyl derivatives.
Thus it was decided (Scheme 19) to attempt the synthesis of the isocyanide derivative
(73). This synthesis involved the use of commercially available 2-benzoxazolinone
(69) as starting material with the potential of being converted via the nitro compound
I II NO2 + O:N >==o (i) p
NO2
(68)
(69) 0
(70)
H
t4—CH=O
NH2
(72)
(71)
NEC
(73)
Nall, DMF, 100°C. H2, Pd-C, DMF, room temp, atmos press. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp.
Scheme 19
23
(70) into the fused diphenylamine isocyanide derivative (73). It was anticipated that
the latter could be cyclised via the corresponding isocyanide dihalide to give a
dibenzodiazepine derivative in which the fused oxazolinone ring would effectively
function as a 5-N-protecting group capable of deprotection by hydrolytic cleavage.
The first step of the synthesis (Scheme 19) of the isocyanide (73) was the reaction of
2-fluoronitrobenzene (68) with the sodium salt of 2-benzoxazolinone (69) to give the
nitrophenylbenzoxazolinone derivative (70). This compound was obtained in good
yield (80%) and analysed correctly and showed mass, i.r. and 'Hn.m.r spectra
consistent with its assigned structure.
Reduction of the nitro compound (70) in dimethylformamide using hydrogen over
palladium-on-charcoal gave the desired amine (71) in quantitative yield. The
analytical and spectroscopic properties of this compound were fully in accord with its
assigned structure. The amine (7 1) in turn reacted as expected with formic acid under
reflux to give a good yield (85%) of the expected formamide derivative (72). The
formamide (72) gave a combustion analysis and mass, i.r. and 'Hn.m.r spectra entirely
consistent with the assigned structure. The next step in the synthesis was the
dehydration of the formamide (72) to give the isocyanide (73). The formamide (72)
reacted, as expected, with phosphoryl chloride and diisopropylethylamine in
dichloromethane at room temperature to give an excellent yield (92%) of the required
(74)
1.01
0 - Th
U
d
Br
N C Br
(75)
(76)
Br2, CH202, -10°C. AIBr3 , CH202, reflux.
Scheme 20
"S ' C
NH2 N'
0 0
(71) (77)
or (iii)
H S Ii
N—(
0
(78)
C12 S, HC1, room temp. AIC13 , CH202, room temp or reflux. AIBr3, CH202, reflux.
Scheme 21
24
isocyanide derivative (73). This previously undescribed compound showed accurate
mass, i.r. and 'Hn.m.r spectra consistent with its assigned structure.
Having successfully obtained the isocyanide derivative (73) its conversion (Scheme
20) to the isocyanide dibromide (74) was next attempted. Thus the isocyanide
derivative (73) was reacted with bromine in dichloromethane at -10°C. The reaction
afforded a product whose high resolution mass spectrum was consistent with the
isocyanide dibromide structure (74). With the isocyanide dibromide (74) readily
available the key step of the synthesis namely its Lewis acid catalysed cyclisation
could now be attempted. Unfortunately reaction of the isocyanide dibromide (74)
with aluminium tribromide under reflux yielded a complex mixture of intractable
gums. It is unclear why the cydlisation did not succeed, perhaps the lack of
cyclisation was due inpart to lack of activation of the benzene ring towards cydlisation
due to the electron withdrawing acyl group or steric effects i.e. the benzene ring may
be unable to align in the correct position for cyclisation.
Having failed to achieve the cycisation [(74) -> (75)] it was decided in passing to
investigate the alternative Lewis acid - catalysed cyclisation (Scheme 21) of the
isothiocyanate derivative (77). Cydlisation reactions of this type to dibenzodiazepine
derivatives are illustrated (Scheme 22) by the transformation [(79) -)~ (80)]
demonstrated in the course of other studies at Edinburgh by Bell. In the present
studies the amine (71) prepared before was reacted with thiophosgene in acetic acid in
S c
co
Me Me
(79)
(80)
(i) Aid 3, CH202, room temp.
Scheme 22
c NO2
(81)
Ii' N—CHO
C 1 ---9
(82)
(83)
i) or (iv)
-I- 1 -
ci (84)
H2, Pd-C, EtOH, room temp, atmos press. HCO2H, reflux. Ph3P, Cc4, Et3N, C1(CH2)2C1, 60°C. POC13 , Pr'2NEt, CH202, room temp.
Scheme 23
25
the presence of aqueous hydrochloric acid to give a product in good yield (75%)
which analysed correctly and gave mass, 'Hn.m.r and i.r. spectra in accord with its
formulation as the isotbiocyanate derivative (77). With this compound readily
available its Lewis acid catalysed cydlisation to the oxazolodibenzodiazepinethione
derivative (78) with aluminium trichioride in dichioromethane at room temperature or
under reflux gave only complex mixtures which yielded no identifiable material. The
attempted cyclisation of the isothiocyanate (77) by heating under reflux with
aluminium tribromide in dichloromethane gave a similar result.
Due to the lack of success in obtaining the fused dibenzodiazepine derivative (75) it
was decided to apply the synthetic strategy illustrated in Schemes 19 and 20 to the
synthesis (Scheme 23 and 24) of the isocyanide dibromide derivative (85). The use of
the triazole system not only had the 5-N position protected throughout the reaction
strategy there was also the ability for the cleavage of the triazole ring via a diazonium
derivative (88). Initially the nitro derivatives (81) and (91) were synthesised (Scheme
25) by reaction of 2-fluoronitrobenzene (68) with the sodium salt of benzotriazole
(90) in dimethylformamide at 100°C. The reaction proceeded as expected to yield the
known derivatives (81) and (91).37 Out of the isomers obtained only 1-(2-
nitrophenyl)benzo- 1,2,3 -triazole (81) had the potential to be used in the general
synthetic strategy of the isocyanide dibromide derivative (85).
ci
Br
NBr
1 ---9 NN
(84) (85)
C .4 ----------
Br
cs ':N p NN
(87)
(86)
0 ci9
H NX III N
(88)
-
C C 'N
(89)
(R = OH, Hal,, etc)
(i) Br2, CH202, - 10°C.
Scheme 24
NO2 N (81)
(I)
I I + N Ir +
N
H NO2
(68) (90) N
(91)
(i) NáH, DME, 100°C.
Scheme 25
26
Catalytic reduction of the nitro derivative (81) also proceeded as expected, in
quantitative yield, to give the known 37 amine compound (82). The latter reacted with
formic acid under reflux to give an excellent yield (100%) of the expected formamide
(83). This previously undescribed compound analysed correctly and showed mass, i.r.
and 'Hn.m.r spectra consistent with its assigned structure.
Having successfully obtained the formamide derivative (83) the next step of the
synthesis was the dehydration of this compound to give the isocyanide derivative (84).
The formamide was therefore reacted with phosphoryl chloride and
diisopropylethylamine in dichloromethane at room temperature to give a poor yield
(14%) of the required isocyanide derivative (84). The isocyanide (84) analysed
correctly and showed spectroscopic properties which fully support its assigned
structure. The use of triphosgene ini ,2-dichloroethane in the presence of
triethylaniine improved the yield of the isocyanide (84) to (38%).
With the isocyanide compound (84) to hand the key intermediate in the synthetic
strategy (Scheme 24), namely the isocyanide dibromide (85) could be synthesised. In
practice reaction of the isocyanide (84) with bromine in dichloromethane at -10°C and
gave an excellent yield (88%) of the required isocyanide dibromide (85). The high
resolution mass spectrum of the product was consistent with the iso cyanide dibromide
structure (85).
27
Having successfully obtained the isocyanide dibromide (85) its cyclisation to the
dibenzodiazepine derivative (86) was next investigated. The isocyanide dibromide
(85) was therefore treated with aluminium tribromide in dichioromethane under reflux
unfortunately this reaction yielded a series of intractable gums which showed no
evidence for the formation of the desired cyclic product (86). Again it is not clear
why the cydlisation was unsuccessful, it is thought that perhaps the benzene ring is
hindered sterically and cannot align in the correct position for cyclisation or that the
electron withdrawing triazole ring deactivates the site of cyclisation.
Previous studies at Edinburgh 2' had shown that dibenzoheteropine derivatives could
be obtained by direct cyclisation of the appropriate isocyanide derivative using
titanium tetrachloride as a Lewis acid catalyst. It was therefore decided to investigate
this type of cyclisation in the case of the isocyanide derivative (84). If successful this
would lead to the dibenzodiazepine derivative (86; H for Br). The isocyanide
derivative (84) was therefore heated under reflux with titanium tetrachloride in
dichloromethane. Unfortunately this reaction gave only a low yield of the amine (82)
with no evidence for the formation of the hoped for dibenzodiazepine derivative (86;
H for Br). It is not immediately obvious how the amine (82) is formed under these
conditions. One possibility is that it results from the hydrolysis of a titanium
tetrachloride complex of the isocyanide (84) on aqueous work up.
NO2 N II +
O:N )
H (68) (92)
NO2 (I)
(93)
F1 N—CHO
(iii) or (iv)
(95) (94)
(v) , or (vii)"\
NC
(96)
NaH, DMF, 100°C SnC12, THF, HC1, reflux. HCO2H, neat or solvent, reflux. HCO2Bu,, reflux. POC13 , Pr'2NEt, CH202, room temp. Ph3P, CC14, Et3N, C1(CH2)2C1, 60°C. (CF3 SO2)20, Pr' 2NEt, CH202, -78°C.
Scheme 26
Br
N*C Br
C)LN - -
(96) -
(97)
S. S.
S. S.
S. S.
Br
S. S.
S. S.
S. S.
----- -----
C CN
11
(98)
(99)
Scheme 27
28
The failure of either the isocyanophenyltriazole (84) or its isocyanide dibromide
derivative (85) to undergo Lewis acid catalysed cyclisation was disappointing and the
reason for the lack of cyclisation not immediately obvious. As already suggested it is
possible that electron - withdrawal by the triazole ring deactivates the 7 - position in
the compound (84) and (85) to electrophilic attack and hence cydlisation. To explore
this possibility it was decided to investigate the synthesis (Schemes 26 and 27) and
cydlisation of the isocyanophenylbenzimidazole (96) and its isocyanide dihalide
derivative (97). It was hoped that the expected lesser electron withdrawing effect of
the imidazole ring in the isocyanide dihalides (97) would facilitate their Lewis acid -
catalysed cyclisation to the corresponding halo genoimidazodibenzazepines (98) and
thence amino derivatives of the type (99).
Initially the known 38 1 -(2-nitrophenyl)benzimidazole (93) was synthesised by reaction
of 2-fluoronitrobenzene (68) with the sodium salt of benzimidazole (92). This
reaction gave only a moderate yield (41%) of the required nitrophenylbenzimidazole
derivative (93) whose melting point agreed with that recorded in the literature. 38
Reduction of the nitro compound (93) with stannous chloride in aqueous
tetrahydrofuran in the presence of hydrochloric acid gave the amine (94) in excellent
yield (96%). This previously undescribed compound analysed correctly and showed
mass, i.r. and 'H n.m.r. spectra which confirmed its identity.
+
(i)
NO2
H çs (68)
(100)
(102)
(ii)
H IF
N—CH=O NH2
c1Nç?
(104) \\ (103)
cCç
& s (105)
NaH, DMF, 100°C. SnC12, HCI, THF, room temp. HCO2H, reflux. POC13, Pr'2NEt, CH2C12, room temp.
Scheme 28
29
The attempted formylation of the amine by heating under reflux in formic acid
afforded a single product in poor yield (42%) whose high resolution mass spectrum,
i.r. and 'H n.m.r. spectra showed it to be the expected formamide (95). The use of
formic acid in toluene with azeotropic removal of the water formed as a by product in
a Dean and Stark apparatus gave a reduced yield of the formamide (95) (32%). In
contrast heating the amine (94) under reflux in butyl formate gave a substantially
improved yield (63%) of the formamide (95).
With the formamide (95) to hand the synthesis of the isocyanide (96) was next
attempted using standard conditions. However this reaction and further reactions
using triphenyiphosphine and carbon tetrachloride in 1 ,2-dichloroethane and also
triflic anhydride and diisopropylethylamine in dichioromethane yielded only complex
mixtures with no evidence for the formation of the isocyanide (96). Having failed to
synthesise the isocyanide the investigation of the synthesis of the
halogenoimidazodiberizaepines (98) was terminated at this point.
In parallel with the foregoing attempts to synthesise and investigate the Lewis acid -
catalysed cyclisation of isocyanide dihalide derivatives of benz-fused five-membered
heterocycles the synthesis and Lewis acid - catalysed cycisation (Schemes 28 and 29)
of the 1,1 -Dibromo- 1 0-(phenothiazin- 1 -yl)phenyhnethanimine (106) was studied. It
was hoped that this molecule with its two benzene rings would be better aligned for
cyclisation and also its enhanced electron - donating capacity of the thiazine ring in
Br
N*C Br
CN
(105)
----- -----
(106)
C
& s
Br
& s (107)
(108)
Br2 , CH202, room temp. AIBr3 , CH202, room temp or reflux.
Scheme 29
30
the phenothiazine derivative (106) would facilitate its Lewis acid - catalysed
cyclisation to the halogenobenzothiazininodibenzodiazepine (107). The general
strategy for the synthesis of the requiredisocyanide dibromide derivative (106)
followed that already described for the five - membered analogues (74), (85), and
(97). The previously undescribed nitro compound (102), amine (103), formamide
(104), and isocyanide (105) were prepared using standard procedures in uniformly
high yield.
Having successfully obtained the isocyanide derivative (105) its conversion (Scheme
29) into the isocyanide dihalide derivative (106) was next attempted. In practice,
reaction of the isocyanide (105) with bromine in dich.loromethane at -10°C gave a
quantitative yield of the required isocyanide dibromide derivative (106). The
structure of this relatively unstable compound was verified by its high resolution mass
spectrum.
The next, and key step, of the synthetic strategy was the Lewis acid - catalysed
cyclisation of the isocyanide dibromide derivative (106) hopefully to give the
dibenzodiazepine derivative (107). In practice the attempted cyclisation of the
isocyanide dibromide derivative (106) by heating with aluminium tribromide in
dichloromethane under reflux did not proceed as expected. This reaction afforded
only a complex mixture with no evidence for the formation of the
benzothiazinodibenzodiazepine derivative (107). Repeating the above reaction but at
"S
NH2 N
N
(i)
N
&s çs
/ (103) (109)
H S N
&s (110)
C12 S, room temp. AIC13, CH202, room temp or reflux.
Scheme 30
31
room temperature also yielded a complex mixture which was not further investigated.
In this case the failure of the isocyanide dibromide derivative to cyclise is probably
more steric than electronic. Although there is the potential for cydlisation to occur on
either benzene ring it is thought that neither benzene ring moves into the necessary
alignment for cyclisation to occur.
Having been unsuccessful in obtaining the dibenzodiazepine derivative (107) it was
decided in passing to investigate the alternative Lewis acid - catalysed cyclisation
(Scheme 30) of the isothiocyanate derivative (109). Thus the amine (103) prepared
before was reacted with thiophosgene in acetic acid in the presence of aqueous
hydrochloric acid to give a product in good yield (8 1%) which analysed correctly and
gave mass, 'H n.m.r. and i.r spectra in accord with its formulation as the thiocyanate
derivative (109). With this compound readily accessible its Lewis acid catalysed
cyclisation to the isothiocyanate (I 10) with aluminium trichloride in dichloromethane
at room temperature and under reflux gave only complex mixtures which yielded no
identifiable material.
In summary only one of the attempted Lewis acid catalysed cyclisation reactions gave
the desired product i.e the cyclisation of the N-ethoxycarbonyl, 1, 1 -Dibromo-N-
(benzenamin- 1 -yl)phenylmethanimine (58) to the bromodibenzodiazepine
derivative(59). It is still unclear why other very similar cyclisation reactions did not
occur. It is however believed that the steric orientation of the molecule may hinder the
32
intramolecular cyclisation. Another possibility for the lack of success of the Lewis
acid catalysed cyclisation reactions is the electronic effect of the rest of the molecule
on the actual site of cydlisation. In several reactions attempted the protecting group
would deactivate the site of cydlisation. Therefore even if sterically the molecule was
perfectly aligned for cyclisation to occur, electronically the reaction would not be
feasible.
Although the final cydlisation step requires some further investigation into its
limitations the work in this section has at least established a good general route to
isocyanide and isocyanide dihalide derivatives. Thus being able to relatively easily
obtain the key intermediates to the Lewis acid catalysed cyclisation reactions further
work into the steric and electrical contributions of other similar molecules can be
attempted. Though perhaps a better understanding on the stability and general
reactivity of the isocyanide dibalide derivatives would in turn help to identify suitable
reaction conditions for the Lewis acid cydlisation to the bromodibenzodiazepine
derivatives.
33
2.4 Experimental
General Experimental Details
Infrared spectra were recorded for Nujol suspensions or thin films using a Perkin-
Elmer 781 spectrophotometer. I.r. bands were strong and sharp unless specified as
w (weak), br (broad) or vs (very strong).
'H n.m.r. spectra were measured in the stated solvent at using a Bruker spectrometer.
Signals were sharp singlets unless specified as br (broad); d = doublet; dd = double
doublet; t = triplet; q = quartet; m = multiplet.
Mass spectral and accurate mass data were obtained using A.E.I. MS-902 and Kratos
MS-50TC instruments. Fast atom bombardment (FAB) mass spectra were measured
for matrices in glycerol.
Microanalyses were determined on a Carlo-Erba Strumentazione Elemental Analyser
MOD 1106. Melting points (m.p.) of all analytical samples were determined on a
Kofler hot-stage and are uncorrected.
All organic extracts were dried over anhydrous magnesium sulphate prior to
evaporation under reduced pressure. Solvents were technical grade unless otherwise
specified and unless otherwise indicated light petroleum had b.p. 60 - 80°C.
34
Wet column flash-chromatography was carried out over silica (Merck grade 60, type
9385). T.1.c. was carried out using Polygram Sit GIUV254 precoated plastic sheets.
N-Phenyl 4-chloro-2-nitrobenzenamine (46).
A solution of 2,5-dichloronitrobenzene (44) (38.4g; 0.2mol) in aniline (45)(160g;
1 .7mol) was stirred and heated under reflux then treated with fused sodium acetate
(3.0g), added in one portion and the mixture was stirred and heated under reflux for
lh. A further nine portions of fused sodium acetate (9 x 3.0g) were added at the end
of each hour and the mixture stirred and heated under reflux for a total time of lOh.
The cooled mixture was distilled to remove unreacted aniline and the residue was
treated with water (200m1) then extracted with dichloromethane (4 x 60.Oml) to give
a dark brown oil (62.8g) which was flash - chromatographed over silica.
Elution with hexane - dichioromethane (4: 1) gave a red oil (3.9g) which was not
further investigated.
Further elution with hexane - dichloromethane (4: 1) gave the nitro derivative (46) as
an orange solid (24.3g; 57%), m.p. 53 - 57°C (lit," imp. 57 - 580C).
35
N-Ethoxycarbonyl, N - phenyl-4-chloro-2-nitrobenzenamine (47).
A suspension of sodium hydride (0.43g ; 0.0 1imol) in anhydrous dimethylformamide
(15.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of the
chloronitrobenzenamine derivative (46) (2.5g ; 0.01mol) in anhydrous
dimethylformamide (10.Oml) and the suspension was stirred at room temperature for
30mm. The mixture was then treated, in one portion, at room temperature, with a
solution of ethyl chloroformate (1.2g; 0.01 imol) in anhydrous dimethylformamide
(5.0ml) and the mixture was stirred at room temperature for lh.
The mixture was treated with water (2.5m1), and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (20.0ml) and
extracted with dichloromethane (3 x 20.0 ml) to give a red - orange oil (3.1g) which
was flash - chromatographed over silica.
Elution with hexane - dichloromethane (4: 1) gave a red oil (0.31g) which was not
further investigated.
Further elution with hexane - ethyl acetate (4: 1) gave the N-ethoxycarbonyl
compound (47) (2.5g; 78%)as an orange oil, b.p.150°C/ 0.05mniHg, v 1720 (CO),
1544 and 1378 (NO2) cm', 8 H 7.96 (1H, d, J 2.511z, ArH), 7.49 - 7.12 (711, m, AM),
4.21 - 4.12(2H, q, J 7.1 Hz C112), and 1.21 - 1.16 (311, t, J 7.1 Hz, C113).
36
Found: C,55.9; H, 4.4; N, 8.5%; mlz (El ms), 320 (1M1 4),
CI5H10requires: C, 56.2; H, 4.1; N, 8.7%; M, 320.
Final elution with methanol gave a brown gum (0.18g) which was not further
investigated.
N-Ethoxycarbonyl. N-Phenyl-4-chlorobenzene-1.,2-diamine (48).
(a) A solution of the nitro compound (47) (1.6g; 0.005mol) in glacial acetic acid
(25.0ml) was hydrogenated over Raney nickel (0.16g) at room temperature and
atmospheric pressure for 2h during which time 561m1 hydrogen was absorbed.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
a green oil which was washed with 10% w/v aqueous sodium hydrogen carbonate
solution (15.Oml). A green solid was observed and collected, the solid was then
dissolved in ethanol and flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave the amino compound (48) (0.60g;
45%) which formed colourless crystals m.p. 129 - 131 °C (from cyclohexane), Vmax
3463 and 3362 (NH) and 1709 (C0) cm', (CDC13) 7.30 - 6.73 (8H, m, AM),
4.20 (2H, q, C112), 3.83 (2H, s, NH2) (exch.) and 1.23 (3H, t, CH3).
37
Found: C, 61.8; H, 5.1; N, 9.4% ; m/z (FAB ms), 291 (MW)
cJ15dll1zQ requires: C, 62.0; H, 5.2; N, 9.6%; M, 290.
(b) A solution of the nitro compound (47) (1.3g ;0.004mol) in tetrahydrofuran
(40.Oml) was stirred and treated with a solution of stannous chloride dihydrate (4.0g;
0.01 8mol) in 2M aqueous hydrochloric acid (40.0ml) and the mixture was then stirred
and heated under reflux for lh.
The mixture was then treated with 30% w/v aqueous sodium hydroxide solution
(32.Oml) and stirred at room temperature for 15 min then concentrated by rotary
evaporation and extracted with ether (3 x 50.Oml) to give the amine derivative (48) as
a colourless solid (0.87g; 75%), m.p. 119 - 123°C identified by comparison (nip. and
i.r. spectrum) with an authentic sample, prepared in (a) before.
N-Ethoxvcarbonvi N-Phenyl 4-chloro-2-formamidobenzenamine (49).
(a) A solution of the amino compound (48) (0.87g ; 0.003mol) in 98 - 100% formic
acid (10.0 ml) was stirred and heated under reflux for 3h. The mixture was then rotary
evaporated and the residue washed with 10% w/v aqueous sodium hydrogen
carbonate solution (3 x 5.0ml) and extracted with dichloromethane (10.0 ml) to give a
gummy purple solid which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave the formamide (49) (0.30g ; 31%)
which formed pale orange crystals, imp. 130 - 132 0 (from ethanol - cyclohexane),
38
3342 (NH) and 1708 and 1692 (C0) cm', 8 H (CDC13) 9.25 (1H, s, NH)
(exch.), 8.28 - 7.91 (111, in, CO), 7.83 - 7.36 (811, in, ArH), 4.24 (211, q, C11 2), and
1.17 (311, t, CH3)
A solution of amine (48) (0.58g; 0.002mol) in butyl formate (5.0mI) was stirred
and heated under reflux and monitored by T.l.c. After 5h the suspension was rotary
evaporated to give a residue whose t.l.c. in hexane - ethyl acetate (7:3) showed it to
be a complex mixture which was not further investigated.
A solution of the amine (48) (0.58g; 0.002mol) in toluene (10.0ml) containing
formic acid (0.2m1; 0.004mol) was stirred and heated under reflux with azeotropic
removal of the water formed using a Dean - Stark apparatus for Th by which time t.l.c
indicated no further change in the consumption of starting material. The resulting
mixture was rotary evaporated to give a residue whose t.Lc. in hexane - ethyl acetate
(7:3) over silica showed it to be a complex mixture which was not further
investigated.
A solution of amine (48) (2.3g ; 0.008mol) in 98 - 100% formic acid (32.0 ml)
was stirred and heated under reflux for 1K The mixture was rotary evaporated and the
residue washed with 10% w/v aqueous sodium hydrogen carbonate (3 x 16.0ml) then
extracted with dichloromethane (16.0 ml) to give a purple foam (2.2g) which was
flash - chromatographed over silica, but gave only a series of intractable gums.
39
N-Ethoxvcarbonvi N-Phenyl-2-nitrobenzenamine (54)
A suspension of sodium hydride (4.3g ; 0.11 mol) in anhydrous dimethylformamide
(50.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2 -
nitrodiphenylamine (53) (21.4g; 0.lmol) in anhydrous dimethylformaniide (10.0ml)
and the suspension was then stirred at room temperature for 30mm. The mixture was
treated, in one portion, at room temperature, with a solution of ethyl chioroformate
(12.0g; 0.1 imol) in anhydrous dimethylformaniide (50.Oml) and the mixture was
stirred at room temperature for 3h after which time t.l.c indicated that all the starting
material had been consumed.
The mixture was treated with water (30.Oml), and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (200m1) and
extracted with dichloromethane (4 x 50.0 ml) to give a dark orange - brown oil
(28.3g) which was flash - chromatographed over silica.
Elution with hexane - ether (97 : 3) gave unreacted starting material (53) (5.2g; 24%)
m.p. 74 - 76°C, identified by comparison (m.p. and i.r.) with an authentic sample.
Elution with hexane - ether (7 : 3) gave N-ethoxycarbonyl, N-phenyl-2 -
nitrobenzenamine (54) (19.1g; 68%) m.p.57 - 59°C, (lit34 ' 35 56 - 58°C).
40
N-Ethoxycarbonyl N-phenyl-benzene- 1.2-diamine (55)
A solution of N-ethoxycarbonyl, N-phenyl-2-nitrobenzenamine (54) (25.7g ; 0.09
mol) in ethanol was hydrogenated over 10% palladium - on - charcoal (2.6g) at room
temperature and atmospheric pressure for 1.75h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
N-ethoxycarbonyl, N-phenyl-benzene-1,2-diamine (55) (23.Og; 100%) m.p. 86 - 89
°C (lit34 ' 35 87 - 90°C).
N-Ethoxycarbonyi N-phenyl-2-formamidobenzenamine (56)
A solution of N-ethoxycarbonyl, N-phenyl-benzene-1,2-dianiine (55) (10.2g;
0.04mol) in 98 - 100% formic acid (80.0 ml) was stirred and heated under reflux for
3h. The mixture was then rotary evaporated and the residue washed with 10% w/v
aqueous sodium hydrogen carbonate (3 x 60.0mI) and extracted with dichioromethane
(40.0 ml) to give N-ethoxycarbonyl, N-phenyl-2- formamidobenzenamine (56) (8.5g;
75%) which formed colourless crystals, m.p. 114 - 116 °C (from ethyl acetate), v r.
3334 (NH), 1704 and 1680 (C0) cm 1 , 6 H (CDC13) 9.84 (1H, s, NH) (exch), 8.55 -
8.01 (1H, m, CHO), 7.53 - 7.01 (9H, m, ArH), 4.18 (211, q, CH2), and 1.19 (3H, t,
CH3).
41
Found. C, 68.1; H, 5.8; N, 10.3%; m/z (FAB ms), 285
CJN.2Q requires ; C, 67.6; H, 5.6; N, 9.9%; M 284.
N-Ethoxvcarbonyl. N-Phenyl-2-isocvanobenzenamifle (57)
(a) A solution of N-ethoxycarbony1, N-phenyl-2-formaniidobenzenamifle (56) (7.1g;
0.025mo1) in anhydrous dichioromethane (125 ml) was stirred and treated, in one
portion, with diisopropylethylamine (9.4g ; 0.075 mol). The mixture was stirred,
cooled to 0 - 5°C (ice - salt bath) and treated dropwise with phosphoryl chloride
(4.3g ; 0.0275 mol) and stirred at room temperature for 4h.
The deep pink mixture was treated dropwise with 1M aqueous sodium carbonate
solution (125 ml) stirred at room temperature for lh then the dichioromethane layer
was separated and washed with water (125m1). The aqueous mother liquor was
extracted with dichloromethane (62.5 ml) and the combined dichioromethane extracts
rotary evaporated to give a brown oil (6.6g) which was flash - chromatographed over
silica.
Elution with hexane - ethyl acetate (7 3) gave the isocyanide (57) (4.9g; 74%) as a
brown oil, v 2122 (NC) and 1714 (CO) cm', (CDC13) 7.47 - 7.16 (911, in,
ArH), 4.25 (2H, q, C112) and 1.25 (311, t, C113)
42
Found ; C, 71.8; H, 5.7; N, 10.3%; m/z (El ms), 266 (M).
HiLzQz requires ; C, 72.2; H, 5.3; N, 10.5%; M 266.
(b) A solution of N-ethoxycarbonyl, N-phenyl-2-forniamidobenzenamine (56) (1.42g;
0.005mol) in anhydrous dichloromethane (37.5m1) was stirred and treated, under
nitrogen at 10°C (ice bath), with a solution of triethylamine (I .0g; 0.Olmol) in
anhydrous dichioromethane (6.Oml) followed by a portion of triphosgene (0.50g;
0.0017mol) in anhydrous dichioromethane (6.0ml). The mixture was then heated
under reflux for 1.5h.
Rotary evaporation gave a brown residue which was treated with water (25.Oml) then
extracted with dichloromethane (3 x 20.0ml) to give a brown gum (1.4g) whose t.I.c
in hexane - ethyl acetate (7 : 3) over silica showed it to be a complex mixture which
was not further investigated.
N-EthoxvcarbonyL 1j-Dibromo-N-(benzenamin-1-vI)phenvlmethanimine (58)
A solution of N-ethoxycarbonyl, N-phenyl-2-isocyanobenzenamine (57) (0.27g;
0.001mol) in anhydrous dichioromethane (10.0ml) was cooled to -78°C (solid CO2 -
acetone) then treated dropwise with a solution of bromine (0.18g ; 0. 00 11 mol) in
anhydrous dichioromethane (10.Oml). The mixture was stirred at -78°C (solid CO 2 -
acetone bath), under nitrogen for 0.5h after which time t.l.c indicated that all the
starting material had been consumed and the mixture was rotary evaporated to give
43
N-Ethoxycarbonyl, 1,1 -Dibromo-N-(benzenaniin- 1 -yl)phenylmethanimine(58)
(0.43g; 100%) as a brown oil.
Accurate mass:
Found :m/z (FAB ms) 424.9531 (MEl4)
ii4rzNQareures 424.9500.
Found m/z (FAB ms)426.9490 (MH)
c,i479Br81 BN202 requires 426.9481.
Found m/z (FAB ms) 428.9477 (MIH)
Ci6ijNZQ2 requires 428.9462.
1 1-Bromo-5-ethoxycarbonyldibenzolbfl -14diazepine (59)
(a) A solution of N-ethoxycarbonyl, N-phenyl-2-isocyanobenzenaniine (57)
(0.53g) ; 0.002mol) in anhydrous dichioromethane (10.Oml) was stirred, under
nitrogen, and cooled to -78°C (solid CO2 -acetone) bath then stirred and treated,
dropwise, with a solution of bromine (0.36g ; 0.0022mo1) in anhydrous
dichlorometbane (10.Oml). The mixture was then stirred at -78°C for 0.5h.
The mixture was then stirred and treated with a suspension of aluminium tribromide
(1.lg; 0.004mol) in anhydrous dichioromethane (10.Oml). The mixture was then
44
stirred at -10°C (ice - salt bath) for lh after which time t1c indicated that no reaction
had occurred.
The reaction was stirred and warmed to room temperature for 2h after which time
t.1.c. indicated no reaction had occurred. The reaction was then stirred and heated
under reflux for 19h after which time t.1.c. indicated that reaction had occurred. The
suspension was allowed to cool then poured into 10% w/v aqueous sodium hydrogen
carbonate solution (32.0ml; 0.004mol)) and stirred at room temperature for 15mm.
The mixture was filtered, to remove insoluble aluminium residues, then extracted with
dichloromethane (2 x 10.Oml) to give a brown gum (0.79g) which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave 1 1-Bromo-5-ethoxycarbonyl-
dibenzo[b,f]-1,4diazepine (59) (0.69g) as a brown gum, v 1714 (CO) and 1590
(C=N) cm'.
Accurate mass:
Found m/z (El ms): 344.0162 (M)
requires: 344.0160.
Found m/z (El ms): 346.0132 (M)
NQrequires: 346.0141.
45
(b) A solution of N-ethoxycarbonyl, N-phenyl-2-isocyanobenzenaniine(57) (1.33g) ;
0.005mol) in anhydrous dichioromethane (25.Oml) was stirred, under nitrogen, and
cooled to -78°C ( solid CO2 -acetone bath) then stirred and treated dropwise with a
solution of bromine (0.88g ; 0.0055mo1) in anhydrous dichioromethane (25.0ml). The
mixture was then stirred at -78°C for 0.5h.
The mixture was treated with portions of a suspension of aluminium tribromide (2.8g;
0.Olmol) in anhydrous dichioromethane (25.Oml) then stirred at room temperature for
4h. The resulting suspension was then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (80.0ml; 0.01mol)) and stirred at room temperature for
1 5mm. The mixture was filtered, to remove insoluble aluminium residues, then
extracted with dichloromethane (2 x 25 .Oml) give a brown gum (1.71g) which was
flash - chromatographed over silica.
Elution with hexane - ethyl acetate (4: 1) gave 1 1-bromo-5-ethoxycarbonyl-
dibenzo[b,fl-1,4-diazepine (59) (1.52g; 88%) identified by comparison (i.r spectrum)
with an authentic sample prepared in (a) above.
M.
The Attempted reaction of 1 1-Bromo-5-ethoxvcarbonyl-dibenzo [b,fI-1.4-
diazepine (59) with Sodium Hydroxide.
A solution of 1 1-bromo-5-ethoxycarbonyl-dibenzo[b,f]-1,4-diazepine (59) (0.69g;
0.002mol) in ethanol (1O.Oml) was stirred and treated with 2M aqueous sodium
hydroxide (2.5m1) then heated under reflux for lh.
Rotary evaporation gave a brown oil which was treated with water (10.Oml) then
extracted with dichloromethane (3 x 10.0 ml) to give a brown gum (0.14g).
Trituration of this gum proved to be unsuccessful. T.l.c. in hexane - ethyl acetate (7:
3) over silica showed the gum to be a complex mixture which was not further
investigated.
The Attempted Reaction of 1 1-Bromo-5-ethoxvcarbonvldibenzolbfI -1.4-
diazepine (59) with Piperidine.
A solution of the 11 .bromo-5-ethoxycarbonyl-dibenzo[b,- 1 ,4-diazepine (59) (0.69g;
0.002mol) in anhydrous acetonitrile (10.Oml) was stirred and treated with a solution
of piperidine (0.34g; 0.004mol) in MeCN (5.0ml) then stirred and heated under reflux,
under nitrogen, for 3h after which time t.l.c. indicated all starting material had been
consumed and the mixture was rotary evaporated to give a dark brown gum.
47
The gum was treated with water (5.OmI) then extracted with dichloromethane (3 x
10.Oml) to give a brown gum (0.47g) whose t.l.c. in hexane - ethyl acetate ( 7 : 3)
over silica showed it to be a complex mixture which was not further investigated
N-MethyiN-Phenyl-2-nitrobenzenamine (62)
A suspension of sodium hydride (4.3g; 0.1lmol) in anhydrous dimethylformamide
(50.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2 -
nitrodiphenylaniine (53) (21.4g ; 0.lmol) in anhydrous dimethyllormamide (10.0ml)
and the suspension was then stirred at room temperature for 30mm. The mixture was
treated, in one portion, at room temperature, with a solution of dimethyl sulphate
(50.Og ; 38.0ml; 0.4mol) in anhydrous dimethylformamide (50.0ml) and the mixture
was stirred at room temperature for 17h.
The mixture was treated with a solution of concentrated ammonia (20.Oml) in water
(40.0ml), and stirred at room temperature for 2h then rotary evaporated. The residue
was treated with water (200m1) and extracted with dichloromethane (3 x 100 ml) to
give N-phenyl-2-nitrobenzenamine (62) (22.2g; 97%) as a red oil. v 1542 and 1368
(NO2)cm'.
N-MethyLN-Phenylbenzene-1.2-diamine (63)
A solution of N-methyl,N-phenyl-2-nitrobenzenamine (62) (22.4g ;0.097mo1) in
tetrahydrofuran (500m1) was stirred and treated at room temperature with a solution
48
of stannous chloride dihydrate (bOg; 0.44mo1) in 2M aqueous hydrochloric acid
(500m1). The mixture was then stirred and heated under reflux for lh.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (400m1)
and stirred at room temperature for 15 min then extracted with ether (3 x 500m1).
Rotary evaporation of the combined ether extracts gave N-methyl, N-phenylbenzene-
1,2-diamine (63) (16.2g; 84%) as a brown oil, Vmax, 3458, 3304, and 3193 (NH2)
cm 1 .
N-Methyl, N-Phenyl-2-formamidobenzenamine (64)
A solution of N-methyl, N-phenyl benzene-1,2-diamine (63) (11.9g ; 0.06mol) in 98 -
100% formic acid (120 ml) was stirred and heated under reflux for 3h. The mixture
was then rotary evaporated and the residue treated with 10% w/v aqueous sodium
hydrogen carbonate (3 x 90.0ml) and extracted with dichloromethane (60.0 ml) to
give a brown gum which was triturated with ether to give the formamide (64) (7.9g;
58%) which formed colourless crystals, m.p. 97 - 99°C (from ethanol), v 3243
(NH) and 1680 (C=O) cm 1 , 8H (CDC13) 8.51 -8.31 (1H, m, CHO), 7.98 (1H, s,
NH) (exch), 7.33 - 6.59 (911, m, Aril), and 3.20 (3H, s, CH 3)
Found C, 73.9; H, 6.2; N, 12.2%; m/z (El ms), 226 (M d)
CHN,aO reciuires C, 74.3; H, 6.2; N, 12.4%; M 226.
49
N-Methyl.N-Phenyl-2-isocyanobenzenamine (65)
A solution of N-methyl, N-phenyl-2-formamidobenzenamine (64) (0.90g ; 0.004)
in anhydrous dichloromethane (20.0 ml) was stirred and treated with
diisopropylethylamine (1.5g; 0.012 mol) added in one portion. The mixture was
stirred, cooled to 0 - 5°C (ice - salt bath) and treated dropwise with phosphoryl
chloride (0.67g ; 0.0044 mol) then stirred at room temperature for 4h. The deep pink
mixture was treated dropwise with 1M aqueous sodium carbonate solution (20.0 ml)
stirred at room temperature for I then washed with water (20.0ml) extracted with
dichloromethane (10.0 ml) to give a brown oil (0.83g) which was flash -
chromatographed over silica,
Elution with hexane - ethyl acetate (9: 1) gave a brown gum (0.07g) which was not
further investigated.
Elution with hexane - ethyl acetate (4: 1) gave N-methyl, N-phenyl-2-
isocyanobenzenamine (65) (0.39g; 47%) as a brown oil, v 2122 (CN) cm'
A solution of N-methyl, N-phenyl-2-formamidobenzenaniine (64) (1.13g;
0.005mol) in anhydrous 1,2 - dichioroethane (37.5 ml) was stirred and treated, under
nitrogen at 10°C (ice bath), with a solution of triethylamine (1.0g; 0.01mol) in
anhydrous 1,2 - dichloroethane (6.Oml) followed by a portion of triphosgene (0.50g;
50
0. 00 17mol) in anhydrous dichioromethane (6.0ml). The mixture was then heated
under reflux for 1 .5h.
Rotary evaporation gave a brown residue which was treated with water (25.Oml) then
extracted with dichloromethane (3 x 20.0ml) to give a dark brown gum (1.0g) whose
t.l.c in hexane - ethyl acetate (7: 3) over silica showed it to be a complex mixture
which was not further investigated.
(c) A solution of N-methyl, N-phenyl-2-formamidobenzenaniine (64) (1.13;
0.005mol) in anhydrous 1,2 dichloroethane (20.0mI) was stirred and treated with
carbon tetrachloride (0.9g ; 0.006mol) then triphenyiphosphine (1.6g ; 0.006mol) and
the mixture was stirred at room temperature for 15 mm. Triethylamine (1 .Og;
0.Olmol) was then added and the mixture was stirred at 60°C (oil-bath) for 2.5h.
The dark brown mixture was concentrated by rotary evaporation, to remove the
dichioroethane, to give a dark brown residue which was treated with water (10.Oml)
then extracted with dichiorometbane (3 x 10.Oml) to give a brown oil (3.8g) which
was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (9: 1) gave N-methyl, N-phenyl-2-
isocyanobenzenamine (65) (0.64g; 64%) as a brown oil, identified by comparison (i.r
and t.l.c.) with an authentic sample prepared in (a) above.
51
The Attempted Synthesis of N-Methyl, 11-Dibromo-N-(benzenamin-1-
yl)pheny1methanimine(66)
A solution of N-methyl, N-phenyl-2-isocyanobenzenamine (65) (0.21g ; 0.00 imol) in
anhydrous dichloromethane (10.Oml) was cooled to -78°C (solid CO2 - acetone) then
stirred and treated dropwise with a solution of bromine (0.18g ; 0.0011 mol) in
anhydrous dichioromethane (10.Oml) and the mixture was stirred at -78°C (solid CO2
- acetone bath), under nitrogen for 1 .5h after which time t.l.c indicated that all the
starting material had been consumed and the mixture was rotary evaporated to give a
brown gum (0.29g) whose t.l.c. in hexane - dichloromethane (1: 1) over silica
showed it to be a complex mixture which was not further investigated.
N-(2-Nitrophenyl)benzoxazolin-2-one (70)
A suspension of sodium hydride (5.3g ; 0.22mo1) in anhydrous dimethylformamide
(40.0ml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2-
benzoxazolinone (69) (27.Og ; 0.2mol) in anhydrous dimethylformamide (80.0mI).
The suspension was then stirred at room temperature for 15mm. The mixture was
treated, in one portion, at room temperature, with a solution of 2-fluoronitrobenzene
(68) (28.Og; 0.2mol) in anhydrous dimethylformamide (20.0mI) and the mixture was
stirred and heated at 100°C (oil-bath) for lh.
The mixture was cooled, treated with water (40.0ml), and stirred at room temperature
for 15min then rotary evaporated. The residue was treated with water (1 60m1) and
OGH
LU
52
extracted three times with dichioromethane (3 x 80.0mI) to give N-(2-nitrophenyl)-2-
benzoxazolinone (70) (40.6g ;79%) which formed yellow crystals, nip. 166 - 168°C
(from acetic acid), u 1520 and 1349 (NO2) cm', ô [(CD3)2 SO] 8.32 (1H, d, J
7.9 Hz, AM), 8.07 - 7.82 (3H, m, AM), 7.56 - 7.50 (1H, m, ArH), 7.31 - 7.21 (2H,
m, ArH) and 7.11-7.04 (1H, m, ArH).
Found: C, 60.9; H, 2.8; N, 10.9%; m/z (El ms), 256 (M).
j2 requires: C, 60.9; H, 3.1; N, 10.9%; M 256.
N-(2-Aminophenyflbenzoxazolin-2-one (71)
A solution of N-(2-nitrophenyl)benoxazolinone (70) (17.9g ; 0.07 mol) in
dimethylformaniide was hydrogenated over 10% palladium - on - charcoal (I. 79g) at
room temperature and atmospheric pressure for 8.5h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
N-(2-aminophenyl)benzoxazolin-2-one (71) (15.8g; 100%) which formed pink -
brown crystals m.p. 108- 110° (from toluene), Vm 3475, 3379 and 3164 (NH) and
1752 (C0) cm', 6H(CDC13) 7.30- 7.09 (5H, m, ArH), 6.89-6.82 (3H, m, AM)
and 3.90 (2H, br s, NH2) (exch).
Found: C, 68.7; H, 4.4; N, 12.1% ; mlz (El ms), 226 (M d).
ç o Qrequires: C, 69.0; H, 4.4; N, 12.4%; M 226.
N-(2-Formamidonheuyl)benzoxazolin-2-one (72)
A solution ofN-(2-aminophenyl)benzoxazolin-2-one (71) (9.Og ; 0.04mol) in 98 -
100% formic acid (80.0 ml) was stirred and heated under reflux for 3h. The mixture
was then rotary evaporated and the residue washed with 10% w/v aqueous sodium
hydrogen carbonate and extracted with dichloromethane (40.0 ml) to afford N- (2 -
formaniidophenyl)-2-benzoxazolinone (72) (8.6g; 85%) which formed light brown
crystals, nip. 149 - 150 1 C (from ethanol), v 3298 (NH), 1757 and 1672 (C0)
cm', (CDC13) 8.47(1H, d, J 11.1Hz CH), 8.22- 8.09(2H, m, AM) 7.54-7.11
(5H, m, ArH), 6.90 - 6.86 (1H, m, ArE!) and 1.74 (111, s, NH) (exch.).
Found; C, 65.7; H, 4.0; N, 10.7%; m/z (El ms) 254 (M).
requires: C, 66.1; H, 3.9; N, 11.0%; M, 254.
N-(2-Isocyanophenyl)benzoxazotin-2-one (73)
A solution of N-(2-formaniidophenyl)benzoxazolin-2-one (73) (10.2g ; 0.04) in
anhydrous dichloromethane (200 ml) was stirred and treated with
diisopropylethylamine (15.6g ; 0.12 mol) added in one portion. The mixture was
stirred, cooled to 0 - 5°C (ice - salt bath) and treated dropwise with phosphoryl
chloride (6.7g ; 0.044 mol) then stirred at room temperature for 4h. The deep pink
54
mixture was treated dropwise with 1M aqueous sodium carbonate solution (200 ml)
stirred at room temperature for I then extracted with dichloromethane (200 ml) to
give N-(2-isocyanophenyl)benzoxazolin-2-one (73) (8.7g ; 92%) which formed brown
crystals, imp. 147 - 149°C (from toluene), v 2121 (NEC) cm 1 , (CDC13) 7.66 -
7.51 (311, m, ArH), 7.33 - 7.16 (3H, in, AM) and (6.87 - 6.77) (2H, m, ArH)
Found; C, 69.5; H, 3.7;N, 11.4%; m/z (El ms) 236 (M).
C14I{8Q2 requires: C,71.2; H, 3.4; N, 11.9%; M, 236.
1 1-Dibromo-N-(benzoxazolin-2-on-1-yI)phenylmethanimine (74)
A solution of N-(2-isocyanophenyl)benzoxazolin-2-one (73) (0.95g ; 0.004mol) in
anhydrous dichloromethane (20.Oml) was treated dropwise with a solution of bromine
(0.70g ; 0.004 mol) in anhydrous dichloromethane (20.Oml) The mixture was stirred
at -78°C (solid CO 2 - acetone bath), under nitrogen. After 1 .5h tic indicated that all
the starting material had been consumed and the mixture was rotary evaporated to
1,1 -Dibromo-N-(benzoxazolin-2-on- 1 -yl)phenylmethanimine (74) (1.6g ; 100%) as
an oil.
Accurate mass;
Found: m/z (FAB ms), 394.9031 (MH).
C1HiN20a requires : M, 394.903.
55
Found: m/z (FAB ms), 396.9010 (MIfl
c,H 79Br81 BrN2Qa requires : M, 396.9014.
Found: m/z (FAB ms), 398.8990 (MIfl.
requires: M, 398.9005.
N-(2-Isothiocyanatophenyl)benzoxazolin-2-one (77).
A solution of N-(2-aminophenyl)benzoxazolin-2-one (71) (2.26g; 0.01mol) in glacial
acetic acid (40,Oml) was stirred and treated with a mixture of concentrated
hydrochloric acid (5.Oml) and water (5.0ml) then treated dropwise at room
temperature with a solution of thiophosgene (2.4g ; 0.02mol) in glacial acetic acid
(5.0ml). The mixture was then stirred at room temperature for 4h.
The mixture was diluted with water (10.Oml) then extracted with dichioromethane
(30.Oml) to give a dark green gum (3.4g) which was flash - chromatographed over
silica.
Elution with hexane - ethyl acetate (3 : 2) gave N-(2-isothiocyano
phenyl)benzoxazolin-2-one (77) (1.7g ; 63%) which formed cream crystals, m.p. 105
107°C (from cyclohexane), v 2063 (N--C=S) cm', 6 (CDC13) 7.55 - 7.39(4H, m,
Arli), 7.36 - 7.13 (3H, m, ArH) and (6.85 - 6.75) (111, m, ArH)
56
Found; C, 62.4; Fl, 2.9; N, 10.3%; m/z (El ms) 268 (M4).
CI4HNQ S requires: C,62.7; H, 3.0; N, 10.5%; M, 268.
Attempted Lewis Acid Catalysed Cyclisation Reactions of N-(2-
isothiocyanatophenyl)benzoxazolin-2-one (77).
A suspension of aluminium trichloride (0.53g ; 0.004mol) in anhydrous
dichiorometbane (20.Oml) was stirred, under nitrogen, and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of N-(2-
isothiocyanatophenyl)benzoxazolin-2-one (77) (0.54g ; 0.002mol) in anhydrous
dichloromethane (10.Oml). The light brown suspension was then stirred at room
temperature for 4h.
The pink suspension was poured into 10% w/v aqueous sodium hydrogen carbonate
(30.0ml) and stirred at room temperature for 15mm. The mixture was filtered, to
remove insoluble aluminium residues, then extracted with dichloromethane (20.Oml)
to give unchanged starting material (77) (0.36g ; 67%), m.p. 105 - 107°C identified
by comparison (m.p. and ft spectrum) with an authentic sample prepared before.
Repetition of the reaction described in (a) before but under reflux for 4h, followed
by the same work up gave unchanged starting material (77) (0.48g ; 89%), m.p. 104 -
106°C identified by comparison (m.p. and i.r. spectrum) with an authentic sample.
57
Repetition of the reaction described in (a) before but with four equivalents of
aluminium trichioride, followed by the same work up gave unchanged starting
material (77) (0.40g; 74%), imp. 104 - 106°C identified by comparison (nip. and i.r.
spectrum) with an authentic sample.
A suspension of aluminium tribromide (1.12g ; 0.004mol) in anhydrous
dichloromethane (20.0ml) was stirred, under nitrogen, and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of N-(2-
isothiocyantophenyl)benzoxazolin-2-one (77) (0.54g ; 0.002mol) in anhydrous
dichloromethane (10.Oml). The light brown solution was then stirred at room
temperature for 4h.
The orange - brown solution was poured into 10% w/v aqueous sodium hydrogen
carbonate (30.0ml) and stirred at room temperature for 15mm. The mixture was
filtered, to remove insoluble aluminium residues, then extracted with dichloromethane
(3 x 20.0ml) to give a brown gum (0.54g) whose t.Lc in hexane - dichloromethane
(1 :1) showed over silica showed it to be a complex mixture which was not further
investigated.
58
The Attempted Aluminium Tribromide Catalysed Cydlisation Reaction of 11-
Dibromo-N-(benzoxazolin-2-on-1-vl)nhenvlmethanimine (74)
A solution of N-(2-isocyanophenyl)benzoxazolin-2-one (74) (0.94g) ; 0.004mol) in
anhydrous dichioromethane (10.Oml) was stirred, under nitrogen, and cooled to
10°C (ice-salt bath) then treated dropwise with a solution of bromine (0.64g;
0.004mol) in anhydrous dichioromethane (10.OmI). The mixture was then stirred at
-10°C for lh.
The mixture was stirred and treated with portions of a solution of aluminium
tribromide (2.2g; 0.008mol) in anhydrous dichioromethane (30Mm!). The mixture was
then stirred and heated under reflux for 4h.
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (62.0m!; 0.08mol)). The mixture was stirred at room
temperature for 1 5mm. The mixture was filtered, to remove insoluble aluminium
residues, then extracted with dichioromethane (2 x 20.0ml). Rotary evaporation of the
combined dichioromethane extracts gave a yellow - brown gummy solid (1.0g) which
was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) through ethyl acetate to methanol gave only
a series of unresolvable mixtures.
59
1-(2-Njtropheny[)benzo-12,3-triazole (81) and 242-NitrophenyI)benzo-1.23-
triazole (91)
A suspension of sodium hydride (5.2g ; 0.22mo1) in anhydrous dimethylformaniide
(40.Oml) was stirred and treated at 0 - 10°C (ice - bath) with a solution of
benzotriazole (90)(24.Og ; 0.2mol) in anhydrous dimethylforniamide (80.0ml). The
suspension was then stirred at room temperature with the exclusion of atmospheric
moisture for 15 mm. The mixture was then treated, in one portion, at room
temperature with a solution of 2- fluoronitrobenzene (68) (28.Og ; 0.2mol) in
anhydrous dimethylformamide (20.Oml) then stirred and heated at 100°C (oil - bath)
for lh.
The mixture was treated with water (40.0ml) and stirred at room temperature for 15
min then rotary evaporated. The residue was treated with water (1 60m1) and extracted
with dichioromethane (3 x 160.Oml) to give an oily orange solid (37.3g) which was
flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7:3) gave 2-(2-nitrophenyl)benzo-1,2,3,-triazole
(91) (4.6g; 10%) as a pale yellow solid, m.p. 131 - 133°C (lit 37, 132 - 1340C).
Further elution with hexane - ethyl acetate (7:3) gave an unresolvable mixture of the
isomers (81) and (91) as a pale yellow solid (6.1g; 13%), m.p. 106 - 110°C.
Further elution with hexane - ethyl acetate (7:3) gave 1-(2-nitrophenyl)benzo- 1,2,3,-
triazole (81) (22.1g ; 46%) as a pale yellow solid, imp. 112 - 119°C (lit 37, 119 -
1200C), v, 1525 and 1353 (NO2) cm 1 .
Rotary evaporation of the original ether light petroleum mother liquor gave an orange
oil (6.3g) whose tic in hexane - light petroleum (7 : 3) over silica showed it to be a
complex mixture which was not further investigated.
1-(2-Aminophenyl)benzo-123-triazole (82).
A solution of 1-(2-nitrophenyi)benzo-1,2,3-triazole (81) (7.2g ;0.03mol) in glacial
acetic acid (250m1) was hydrogenated over 10% palladium - on - charcoal (0.72g) at
room temperature and atmospheric pressure for 2h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
1-(2-aminophenyl)benzo- 1,2,3 -triazole (82) as a pale brown solid (6.3g; 100%)
m.p. 131 - 133°C (lit37 132- 133 °C), v 3441 and 3339 (NIH2 )cm'.
1-(2-FormamidophenvE)benzo-1.23-triaZOle (83).
A solution of 1-(2-aminophenyl)benzo-1,2,3-triazole (82) (12.6g ; 0.06mol) in 98-
100% formic acid (120m1) was stirred and heated under reflux for 3h.
61
The mixture was rotary evaporated and the residue was washed with 10% aqueous
sodium hydrogen carbonate solution then extracted with dichloromethane (3 x 60m1)
to give 1 -(2-Formaniidophenyl)benzo- 1 ,2,3-triazole (83) (1.2g;100%) which formed
cream crystals, imp. 123-124°C (from toluene), v 3310 (NH) and 1697 (C=O)
cm 1 , E, (CDC13) 8.95 (1H,s,NIH)(exch), 8.58-8.43 (1H, mAr11), 8.3-8.29 (1H,
d,CH), 7.99 - 7.82 (1H, in, ArH) and 7.51 - 7.41 (611, in, Ar11).
Found: C, 65.4; H,4.3; N, 23.3% ; m/z (El ins) , 238 (M).
H10N40 requires : C,65.6; H,4.2; N, 23.5%; M, 238.
1-(2-Isocyanophenyl)benzo-1.2,3-triazole (84).
A solution of 1-(2-formamidophenyl)benzo-1,2,3-triazole (83) (6.Og ; 0.025mo1) in
anhydrous 1,2 dichloroethane (1 OOml) was stirred and treated with carbon
tetrachloride (4.5g ; 0.03mol) then triphenylphosphine (8.Og ; 0.03mol). The mixture
was stirred at room temperature for 15 mm. Triethylamine (10.0g ; 0.lmol) was then
added and the mixture was stirred at 60°C (oil-bath) for 2.5h.
The dark brown mixture was concentrated by rotary evaporation to remove the
dichioroethane to give a dark green residue (19.9g). This was triturated with ethyl
acetate and filtered to remove triphenylphosphine oxide (5.5g), m.p. 190 - 196°C
identified by comparison (imp. and ft spectrum) with an authentic sample.
62
The ethyl acetate filtrate was rotary evaporated and gave a dark brown gum (13.6g)
which was flash-chromatographed over silica.
Elution with hexane-ethyl acetate (7:3) gave 1-(2-isocyanophenyl)benzo-1,2,3-
triazole (84) (2.1g ; 38%) which formed colourless crystals, imp. 118 - 120°C (from
ethanol), v 2121(NC)cm' , 8 (CDC13) 8.19 - 8.18 (1H,mArH), 7.71 - 7.49
(411, n ArH), and 7.47 - 7.41 (3H, m, ArE!).
Found: C, 70.6; H,3.7; N, 25.2% ; m/z (FAB ms) ,221 (MH4 )
cQreguires : C,70.9; H3.6; N, 25.5%; M, 220.
(b) A solution of 1-(2-formaniidophenyl)benzo-1,2,3-triazole (84) (1.2g ; 0.005mol)
in anhydrous dichioromethane (10.0 ml) was stirred and treated with
diisopropylethylamine (2.Og ; 0.015 mol),in one portion. The mixture was stirred,
cooled to 0 - 5° (ice - salt bath) and treated dropwise with phosphoryl chloride
(0.85g ; 0.0055 mol) then stirred at room temperature for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution (12.5
ml), stirred at room temperature for I then extracted with dichloromethane (2 x 10.0
ml) to give a pale brown solid which was flash - chromatographed over silica.
63
Elution with hexane - ethyl acetate (65 : 35) gave the isocyanide (84) (0.16g; 14%),
m.p. 126 - 128°C as a cream solid identified by comparison (imp, and ir spectrum)
with an authentic sample prepared before.
Elution with hexane - ethyl acetate (65 35) gave a brown gummy solid (0.66g)
whose t.1.c. in hexane ethyl acetate (7 : 3) over silica showed it to be a mixture of the
amine (82) and isocyanide (84). Further separation attempts were unsuccessful.
1,1-Dibromo-1-(benzo-1,23-triazol-1-yfløhenvlmethanim me (85).
A solution of 1-(2-isocyanophenyl)benzo-1,2,3-triazole (84)(0.44g) ; 0.002mol) in
anhydrous dichioromethane (10.Oml) was stirred, under nitrogen, and cooled to -10°C
(ice-salt bath) then treated dropwise with a solution of bromine (0.32g ; 0.002mol) in
anhydrous dichioromethane (10.Oml). The mixture was then stirred at -10°C for lh.
Rotary evaporation of the orange reaction mixture gave an orange gum (0.67g) whose
tic in hexane- dichlorometbane (1: 1) over silica showed it to be a single product
identified as the isocyanide dibromide derivative (85).
Found: m/z (FAB ms), 379 (MH) 4
r2N requires : M, 378.
64
Found :m/z (FAB ms), 381 (Ivflf).
CHg79Br81Br N4 requires : M, 380.
Found :m/z (FAB ms), 383 (MH).
requires M, 382.
The Attempted Aluminium Tribromide Catalysed Cyclisation Reaction of
1 . 1-Dibromo- 1-(benzo-1.2.3-triazol-1-yl)Dhenvhpethanimine (85.
A solution of isocyanide dibromide (85) (1.5g; 0.004mol) in anhydrous
dichioromethane (10.0ml) was stirred under nitrogen, and treated, with portions of a
solution of aluminium tribromide (2.2g; 0.008mol) in anhydrous dichioromethane
(30.Oml). The mixture was then stirred and heated under reflux for 4h.
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (62.Oml; 0.08mol)) and the mixture stirred at room
temperature for 1 5mm. The mixture was filtered, to remove insoluble aluminium
residues, then extracted with dichloromethane (2 x 20.0ml) to give an orange - brown
oil (0.55g) which was flash - chromatographed over silica, but gave no identifiable
material.
65
The Attempted Titanium Tetrachloride Catalysed Cyclisation of 142-
Isocyanophenyllbenzo-123-triazole (84).
A solution of 1-(2-isocyanophenyl)benzo-1,2,3-triazole (84) (0.88g ; 0.004mo1) in
anhydrous dichioromethane (20.0ml) was stirred under nitrogen, cooled to 0 - 10°C
(ice-bath) then treated, dropwise, with a solution of titanium tetrachloride (3.8g;
2.2m1 ; 0.02mol) in anhydrous dichioromethane (10.Oml). The mixture was then
stirred, under nitrogen, and heated under reflux for 24h.
The mixture was cooled (ice-bath) and treated with 60% (15M) aqueous sodium
hydroxide solution (13.2m1 ; 0.02mol), stirred for 15 min then diluted with water
(20.0ml). The resulting mixture was filtered to remove insoluble titanium residues
then extracted with dichloromethane (3 x 10.Oml) to give the amine (82) (0.14g;
49%), m.p. 124 - 126°C, identified by comparison (m.p. and i.r spectrum) with
authentic sample prepared before.
N(NitrophenyE)benzimidazole (93)
A suspension of sodium hydride (8.6g ; 0.22mo1) in anhydrous dimethylformamide
(40.0ml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of
benzimidazole (92) (23.6g ; 0.2mol) in anhydrous dimethylformamide (100.Oml). The
suspension was stirred at room temperature for 20mm. The mixture was treated, in
one portion, at room temperature with a solution of 2-fluoronitrobenzene (68)
(28.Og; 0.2mol) in anhydrous dimethylformaniide (20.0ml) and the mixture was
stirred and heated at 100°C (oil-bath) for lh.
The mixture was cooled treated with water (40.0ml), and stirred at room temperature
for 15min then rotary evaporated. The residue was treated with water (160m1) and
extracted three times with dichioromethane (3 x 80.0m1) to give a dark brown oil
(42.0g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7: 3) gave a yellow oil (1.9g) whose t.l.c in
hexane - ethyl acetate (7: 3) showed it to be unreacted 2-fluoronitrobenzene (68).
Elution with hexane - ethyl acetate (3 : 7) gave N-(2-nitrophenyl) - 2 - benzimidazole
(93) (19.6g; 41%) m.p. 80 - 82°C ( lit", 80 - 82 0C), Vmax 1523 and 1352 (NO2) cm'
N42-Aminopheny0benzimidazole (94)
A solution of N-(2-nitrophenyl)benzimidazole (93) (4.8g ;0.02mol) in tetrahydrofuran
(200m1) was treated with a solution of stannous chloride dihydrate (20Mg; 0.09mol)
in 2M aqueous hydrochloric acid (200m1) then stirred and heated under reflux for lh.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (80.0ml)
and stirred at room temperature for 15 mm. The mixture was then extracted with
ether (3 x 250m1) to give N-(2-aniinophenyl)benzimidazole (94) (4.0g; 96%) which
67
formed cream crystals, m.p. 113 - 115°C (from cyclohexane - ethyl acetate), v
3334 and 3210 (NH2) cm', ö (CDC1 3), 7.95 - 6.8 (9H, m, ArH), and 3.61 (2H, s,
N112) (exch).
Found: C, 75.2; H, 5.2; N, 20.2 % ; m/z (El ms),209 (M).
reguires: C, 74.6; H, 5.3; N, 20.1%; M 209.
N-(2-Formamidophenyl)benzimidazole (95'
(a) A solution ofN-(2-aminophenyl)benziniidazole (94) (0.84g ; 0.004mol) in 98-
100% formic acid (10.Oml) was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue was washed with 10% aqueous
sodium hydrogen carbonate solution then extracted with dichloromethane (3 x
1 0.Oml) to give a green gum (0.56g) which was triturated with light petroleum - ether
to give N-(2-formamidophenyl)-2-benzimidazole (95) (0.40g; 42%) which formed
green crystals imp. 160 - 162°C (from ethanol), v 3342 (NH) and 1694 (C0)
cm- 1 ,
Accurate mass;
Found: m/z (FAB ms)238.0961(MH)
CjJO requires : M, 238.0980.
68
A solution of N-(2-aminophenyl)benzimidazole (94) (0.84g; 0.004mol) in
anhydrous toluene (16.Oml) was treated with 98 - 100% formic acid (0.4m1;
0.008mo!). The solution was heated under reflux with azeotropic removal of the
water formed using a Dean - Stark apparatus and monitored by t.l.c in hexane - ethyl
acetate (1: 4) over silica for 22h.
Rotary evaporation, under high vacuum, gave a brown gum which was triturated with
ethyl acetate to give N-(2-formanüdophenyl)benzimidazole (94) (0.30g; 32%) m.p.
159 - 161°C identified by comparison (m.p. and i.r) with an authentic sample
prepared in (a) above.
Rotary evaporation of the ethyl acetate gave a brown gum (0.57g) whose t.l.c in
hexane - ethyl acetate over silica showed it to be a mixture of starting material and
product and was not further investigated.
A solution of N-(2-aminophenyl)benzimidazole(94) (4.2g; 0.02mol) was treated
with butyl formate (50.0ml) and heated under reflux, with the exclusion of
atmospheric moisture, for 90h.
Rotary evaporation, under high vacuum gave N-(2-formamidophenyl)benzinhidazole
(95) (3.0g; 63%), m.p. 160 - 162°C as a colourless solid identified by comparison
(m.p. and i.r. spectrum) with an authentic sample prepared in (a) above.
The Attempted Synthesis of N-(2-Isocyanophenvl)benzimidazoLe (96)
(a) A solution ofN-(2-formamidophenyl)benzimidazole(95) (0.47g ; 0.002mol) in
anhydrous dichioromethane (20.Oml) was stirred and treated with
diisopropylethylamine (0.76g ; 0.006mol), in one portion. The mixture was treated
dropwise with stirring at 0 - 5°C (ice-salt bath) with phosphoryl chloride (0.34g;
0.0022mo1) then stirred at room temperature, with the exclusion of atmospheric
moisture for 4K
The mixture was then treated dropwise with IM aqueous sodium carbonate solution
(10.Oml) and stirred at room temperature for lh. Extraction of the mixture with
dichloromethane (3 x 5.0ml) gave a sticky brown solid which was flash -
chromatographed over silica, but gave no identifiable material.
(b) A solution of N-(2-formamidophenyl)benzimidazole (95) (0.95g ; 0.004mol) in
anhydrous 1,2 dichloroethane (20.Oml) was stirred and treated with carbon
tetrachloride (0.72g ; 0.0048mo1) then triphenylphosphine (1.3g ; 0.0048mol). The
mixture was stirred at room temperature for 15 min. Triethylamine (0.8g ; 0.008mol)
was then added and the mixture was stirred at 60°C (oil-bath) for 2.5h.
The dark brown mixture was concentrated by rotary evaporation to remove the
dichloroethane to give a dark brown oil (2.4g).which was flash-chromatographed
over silica.
70
Elution with hexane-ethyl acetate (3 : 7) gave a brown oil (0.11 g) which was not
further investigated.
Elution with hexane - ethyl acetate (3 : 7) gave a brown gum which was triturated to
give starting material (0.16g; 17%) m.p.159 - 161°C identified by comparison (imp.
and i.r.) with an authentic sample. Evaporation of the ethyl acetate gave a brown gum
(0.26g) whose t.l.c in hexane -ethyl acetate (3 : 7) over silica showed it to be a
mixture which was not further investigated.
Elution with hexane - ethyl acetate (3 : 7) gave a colourless solid which was identified
by comparison (imp. and i.r spectrum) as triphenyl phosphine.
(c) A solution ofN-(2-formamidophenyl)benzimidazole (95) (0.47g ; 0.002mol) in
anhydrous dichioromethane (10.Oml) was cooled to -78°C (solid CO2 - acetone bath)
and treated with a solution of diisopropylethylamine (1.6g; 0.012mol) in
dichloromethane (5.0ml), then treated with a solution of triflic anhydride (0.84g;
0.0035mo1) in anhydrous dichioromethane (5.Oml). The mixture was stirred at -78°C
for 0.5h. The mixture was then treated with a solution of 10% w/v aqueous sodium
hydrogen carbonate (10.0ml).
After warming to room temperature the mixture was extracted with dichioromethane
(2 x 10.Oml). The combined dichloromethane extracts were rotary evaporated to give
71
a brown oil (1.9g) which was washed with 2M aqueous hydrochloric acid (10.Oml)
then extracted with dichioromethane (3 x 10.Oml) to give a brown gum(0.59g) which
was flash - chromatographed over silica, but gave no identifiable material.
10-(2-Nitrophenyl)phenothiazine(102)
A suspension of sodium hydride (2.6g ; 0.11 mol) in anhydrous dimethylformaniide
(20.Oml) was stirred and treated at 0 - 10°C (ice - bath) with a solution of
phenothiazine (100) (19.9g; 0.1mol) in anhydrous dimethylformamide (40.Oml). The
suspension was stirred at room temperature with the exclusion of atmospheric
moisture for 15 mm. The mixture was treated, in one portion, at room temperature
with a solution of 2- fluoronitrobenzene (68)(14.Og ; 0.1mol) in anhydrous
dimethylformamide (10.Oml). The mixture was then stirred and heated at 100°C (oil -
bath) for lh.
The mixture was treated with water (80.Oml) and stirred at room temperature for 15
min then rotary evaporated. The residue was treated with water (80.0ml) and
extracted with dichloromethane (3 x 40.0m!) to give an orange solid which was
triturated with light petroleum to afford 10-(2-nitrophenyl)phenothiazine (102) (27.2g
85%), which formed orange-brown crystals, m.p. 157 - 159°C (from acetic
acid),v1520 and 1349 (NO 2)cm', 8H [(CD3)2S0] 8.31 - 8.27 (1H, d, J 8.0Hz ArH),
8.07 - 7.84 (2H, m, ArH), 7.08 - 6.98 (311, m, ArH), 6.96 - 6.82 (4H, in, AM), and
6.05 - 6.00 (2H, in, ArH).
72
Found: C, 66.9; H, 3.7; N, 8.6%; m/z (El ms), 320(M),
CigHQS requires: C, 67.5; H, 3.8; N, 8.8%; M 320.
10-(2-Aminophenyl)phenothiazine (103)
A solution of 10-(2-nitrophenyl)phenothiazine (102) (25.8g ;0.09mol) in
tetrahydrofuran (900m1) was stirred and treated with a solution of stannous chloride
dihydrate (90.0g; 0.41mol) in 2M aqueous hydrochloric acid (900m1) then stirred and
heated under reflux for lh.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (720m1)
and stirred at room temperature for 15 min then concentrated by rotary evaporation
and extracted with ether (3 x 1000ml) to give 10-(2-aminophenyl)phenothiazine (103)
(24.2g; 93%) which formed cream crystals, imp. 138 - 140°C (from acetic acid), v
3453 and 3366 (NH2) cm', 8H [(CD3SO, 7.25 - 7.11 (2H, m, ArH), 7.02 - 6.70 (8H,
m, ArH), 6.18 - 6.14 (211, m, ArH), and 5.09 (211, s, NH 2) (exch).
Found: C, 73.9; 11,4.9; N, 9.4%; m/z (El ms), 290 (M),
CHS requires: C, 74.4; H, 4.8; N, 9.7%; M 290.
10-(2-Formamidophenyflphenothiazine (104)
A solution of 10-(2-aminophenyl)phenothiazine (103) (2.9g; 0.Olmol) in 98-100%
formic acid (20mi) was stirred and heated under reflux for A. The mixture was then
73
rotary evaporated and the residue was washed with 10% aqueous sodium hydrogen
carbonate solution (3 x20.0ml) then extracted with dichioromethane (3 x 10.Oml) to
give a purple solid (2.7g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave 10-(2-formaniido
phenyl)phenothiazine (104) (2.2g; 70%) which formed grey crystals,
m.p. 194 - 196 °C (from toluene) v 3342 (NH) and 1699 (C=O) cm-', 6, (CDC1 3)
8.65 (1H,S,NIf)(exch), 8.28 - 7.91 (1H, m, CHO), 7.84 - 7.50 (4H, in, ArH), 7.35 -
6.79 (6H, m, ArH), and 6.11 - 6.03 (211, m, ArH).
Found: C, 71.3; H,4.4; N, 8.6%; m/z (El ms), 318 (M).
j0S requires. C,71.7; H,4.4; N, 8.8%; M, 318.
10-(2-Isocyanophenyl)phenothiazine (105)
A solution of 10-(2-formaniidophenyl)phenothiazine (104) (9.5g ; 0.03mol) in
anhydrous dichioromethane (1 5 0ml) was stirred and treated with
diisopropylethylamine (11 .6g ; 0.09mol), in one portion. The mixture was then treated
dropwise with stirring at 0 - 5°C (ice-salt bath) with phosphoryl chloride (5.1g;
0.033mo1) and stirred at room temperature, with the exclusion of atmospheric
moisture for 4h. The mixture was then treated dropwise with 1M aqueous sodium
carbonate solution (lSOml) and stirred at room temperature for lh. Extraction with
74
dichioromethane gave 10-(2-isocyanophenyl)phenothiazine (105) (8.4g; 93%) which
formed colourless crystals, m.p. 131 - 133° (from cyclohexane), v 2124 (NEC)
cm', 6 (CDC13)7.84 - 7.50 (411, m, ArH), 7.35 - 6.79 (6H, m, ArH), and 6.11 - 6.03
(2H, m, Arli).
Found C, 75.8; H, 4.2; N, 9.1% ; m/z (El ms) ,300 (M)
requires : C,76.0; H, 4.0; N, 9.3%; M, 300.
1.1-Dibromo-10-(phenothiazin-1-yI)phenylmethanimine (106)
A solution of 10-(2-isocyanophenyl)phenothiazine (105) (1.2g ; 0.004mol) in
anhydrous dichloromethane (20.Oml) was stirred under nitrogen and cooled to -10°C
(ice - acetone bath) then treated dropwise with a solution of bromine (0.70g ; 0.004
mol) in anhydrous dichloromethane (20.Oml). The mixture was stirred at -10°C,
under nitrogen for lb by which time t1c. indicated that all the starting material had
been consumed. Rotary evaporation gave the isocyanide dibromide derivative (106)
(1.7g; 100%) as a foam.
Accurate mass;
Found: m/z (El ms), 458 (M),
CH!NS requires : M, 458.
75
Found: m/z (El ms), 460 (Md),
C i9H 79Br81 BrNaS requires: M, 460.
Found: mlz (El ms), 462 (M).
C1192H_,28 'BrZN2_.S requires : M, 462.
The Attempted Aluminium Tribromide Catalysed Cyclisation Reaction of 11 -
Dibromo-10-(phenothiazin-1-yl)phenylmethanimine(106)
A solution of the isocyanide dibromide (106) (2.8g; 0.005mol) in anhydrous
dichioromethane (25.0ml) was stirred under nitrogen, and treated, with portions of a
solution of aluminium tribromide (2.8g; 0.Olmol) in anhydrous dichioromethane
(20.Oml). The mixture was then stirred under nitrogen and heated under reflux for 4h.
The dark purple solution was allowed to cool then poured into 10% w/v aqueous
sodium hydrogen carbonate solution (78.0ml; 0.1mol)) and the mixture stirred at
room temperature for 1 5mm. The mixture was filtered, to remove insoluble aluminium
residues, then extracted with dichioromethane (2 x 25.Oml) to give a brown foam
(1.8g) which was flash - chromatographed over silica but gave only a series of
intractable gums and oils which gave no identifiable material.
76
10-(2-Isothiocyanophenyl)phenothiazine (109)
A solution of 10-(2-aminophenyl)phenothiazine (103) (1.45g ; 0.005mol) in glacial
acetic acid (40,0ml) was stirred and treated with a mixture of concentrated
hydrochloric acid (5.OmI) and water (5.Oml) then treated dropwise at room
temperature with a solution of thiophosgene (1.2g ; 0.01mol) in glacial acetic acid
(2.5m1). The mixture was stirred at room temperature for 4h then diluted with water
(25.0ml), then extracted with dichioromethane (50.Oml). The combined
dichioromethane extracts were washed with 10% w/v aqueous sodium hydrogen
carbonate solution (3 x 25.Oml) to give a brown - green gum (1.4g) which was flash -
chromatographed over silica.
Elution with hexane - dichloromethane (9: 1) gave 1 0-(2-isothiocyano
phenyl)phenothiazine (109) (10.8g ; 81%) which formed yellow crystals, m.p. 112 -
114°C (from cyclohexane), v 2033 (N --C=S) cm ' , 6 (CDC13) 7.49 - 7.25 (41-1, m,
ArH), 7.03 - 6.78 (6H, m, ArH) and 6.06 - 5.99 (211, m, ArH)
Found; C, 68.2; H, 3.5; N, 8.3%; m/z (El ms) 332 (Md),
C_19HIINZ Sg requires: C,68.7 ; H, 3.6; N, 8.4%; M, 332
77
Attempted Aluminium Trichlonde Catalvsed Cydisation Reactions of 1042-
Isothiocyanophenyflphenothiazine (109)
(a) A suspension of aluminium trichioride (0.53g ; 0.004mol) in anhydrous
dichlorometbane (20.0ml) was stirred, under nitrogen, and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of 10-(2-isothiocyano
phenyl)phenothiazine (109) (0.66g ; 0.002mol) in anhydrous dichioromethane
(10.Oml). The light brown suspension was then stirred at room temperature for 4h.
The purple suspension was poured into 10% w/v aqueous sodium hydrogen carbonate
(30.0ml) and the mixture stirred at room temperature for 15mm. The mixture was
filtered, to remove insoluble aluminium residues, then extracted with dichloromethane
(3 x 20.Oml) to give an orange solid (0.42g) which was dry flash - chromatographed
over silica, but gave only intractable oils and gums.
(b) Repetition of the reaction described in (a) above but with two equivalents of
aluminium trichloride, followed by the same work up gave a yellow solid (1.3g) which
was found to be a complex mixture by t.l.c. over silica hexane - dichioromethane
(1: 1), and therefore was not further investigated.
78
Chapter Three
Studies of Synthetic Routes to Polycyclic Reteropine and Heterocine
Derivatives based on Isocyanide Dihalide Cyclisation Reactions
OH'23 (68)
(111)
(112)
FI N—CHO
cL (114)
NEC
d O Q\ (115)
Nall, DMF, 100°C. H2, Pd-C, DME, room temp, atmos. pres. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp.
Scheme 31
(113)
79
Studies of Synthetic Routes to Polycyclic Heteropine and Heterocine
Derivatives based on Isocyanide Dihalide Cyclisation Reactions
3.1 Introduction
As already discussed in Chapter 2 isocyanide dihalides have the potential to be used as
key intermediates in intramolecular Friedel - Crafts type cyclisation reactions to form
dibenzodiazepines. In this Chapter attempts to extend such transformations to the
synthesis of benzo [b]naphth[1 ,4]oxazepine derivatives, are described.
3.2 Investigations of Lewis Acid Catalysed Cydlisation Reactions of
2-Naphthyloxvphenvl isocyanidedibromides to Benzolbl naphthoxazepines and
Related Transformations
Initially it was decided to further investigate the potential of the novel Lewis acid
catalysed heterocyclisation reactions of suitable isocyanide dihalides for the general
synthesis of benzo[b]naphthoxazepines. The proposed synthesis (Schemes 31 and 32)
involved the initial formation of 1-(2-nitrophenoxy)naphthalene (112). Thus using the
general synthetic strategy already exploited in Chapter 2 the initially required nitro
compound (112) was synthesised by the reaction of the sodium salt of l-naphthol
(I 11) with 2-fluoronitrobenzene (68) in dimethylformamide at 100°C. The nitro
compound (112) was obtained in excellent yield (89%) and its melting point and i.r.
34 spectrum were identical to those described in the literature Catalytic reduction of
the nitro derivative (112) also proceeded as described in the literature to afford the
- NC
N
\/ (115)
Hall Hal l
N Hal 3
c '
°Ô +
116 Hal' Ha12 117 Hal' Ha12 Ha13 Br Br a; Br Br Br Br Cl b; Br Cl Br
C; Cl Cl Br
Hal
V -.\N
Hal l N
c K>( H a 1 2
+
118 Hal 119 Hal' Hal' Br a; Br Br Cl b; Cl Br
C; Cl Cl
Br2, solvent, -78°C. AIBr3, solvent, room temp or reflux.
Scheme 32
80
known 14 amine derivative (113) in high yield (89%). Reaction of the amino
compound (113) with formic acid under reflux afforded a product which analysed
correctly and gave mass, 'H n.m.r., and i.r. spectra consistent with its formulation as
the expected formaniide (114).
The next step in the synthetic strategy was the dehydration of the formamide (114) to
obtain the isocyanide (115). The formamide (114) was therefore reacted with
phosphoryl chloride in the presence of diisopropylethylamine in dichioromethane at
room temperature to give a good yield (80%) of the required isocyanide derivative
(115). This previously undescribed compound analysed correctly and showed mass,
i.r. and 'H n.m.r. spectra consistent with its assigned structure.
Having successfully obtained the isocyanide derivative (115), its conversion (Scheme
32) into the isocyanide dibromide (1 16a) was next attempted. The isocyanide
derivative (115) was therefore treated under standard conditions with bromine in
dichioromethane at -78°C to give a product whose mass spectrum indicated the
presence of not only the required isocyanide dibromide (1 16a) but also the isocyanide
bromochioride (1 16b) as well as a bromo-isocyanide dibromide (1 17a), a bromo-
isocyanide bromochloride (11Th), and a bromo-isocyanide dichloride (1 17c). The
formation of the ring brominated products (I 17a -c) was completely unexpected as
was the apparent chlorination of the isocyanide group required by the production of
the compounds (1 16b), (11Th), and (1 17c). The formation of the latter three products
Hal l Hal l
N' N* Hal 3
)5+ cL) c'
\/
116 Ha!' Ha!2 117 Ha!' Ha!2 Ha!3 Br Br a; Br Br Br Br Cl b; Br Cl Br
C; Cl Cl Br
N, N
N
Hl
N
N' a N Hal Br
i '
\ I
(120) Hal (121) Br Cl
(i) Nali, DME, room temp.
Scheme 33
81
requires the involvement of the dichioromethane solvent in some way or traces of
hydrochloric acid present as an impurity. Though the position of the ring bromo-
substituents in the products (1 17a - c) has not been established it is assumed that the
more readily brominated naphthalene ring rather than the benzene ring is involved.
Naphthalene ring - bromination (as distinct from chlorination) and hence the siting of
the chioro - substituents on the iso cyanide group was subsequently established as
described below.
With a view to establishing the respective positions of the bromo- and chioro -
substituents in the mixture while at the same time simplifying it to facilitate separation
into single characterisable components, it was decided to subject the mixture to
reactions which would convert the isocyanide dihalide groups present into stable end -
products (for examples of such reactions see chapter 2, section 2.1). An attempt was
therefore made to react (Scheme 33) the isocyanide dihalide mixture (1 16a and b) and
(1 17a - c) with sodium azide in 1,2-dimethoxyethane at room temperature. It was
hoped, that this reaction would give a separable mixture of the tetrazole products
(120a and b) and (121a and b). In practice the mixture obtained could not be
separated into identifiable products. However the mass spectrum of the tetrazole
mixture indicated the presence of only the bromotetrazole (120a), the chiorotetrazole
(120b) and the dibromotetrazole (121). This result verifies that in the original mixture
the halogen in the benzene ring was only bromine.
Hal l Hal l
N N' Hal 3
d' +
(116) Hal' Hal2 (117) Hal' Hal2 Ha!3 Br Br a; Br Br Br Br Cl b; Br Cl Br
C; Cl Cl Br
H U
H N H N
N N Br
+ CO
(122) (123)
(i) o-phenylenediamine, CH2 Cl2 , 0°C.
Scheme 34
Hal l Hal l
WO, C-Hal2
N Hal 3
+
(116) Hal' Hal2 (117) Hal' Hal2 Hal3 Br Br a; Br Br Br Br Cl b; Br Cl Br
C; Cl Cl Br
No No I I /D
N' N'
+
(Br
(124) (125)
(i) piperidine, C11202, 0°C.
Scheme 35
82
In a further attempt (Scheme 34) to clarify the nature of the isocyanide dihalide
mixture it was reacted with ortho-phenylenediamine in dichioromethane in the
presence of triethylamine in the hope of obtaining the benzimidazole derivatives (122)
and (123). Unfortunately this reaction afforded only an intractable brown gum which
was shown by t.l.c. to be a complex mixture and therefore was not further
investigated. The attempted reaction (Scheme 35) of the isocyanide dihalide mixture
with piperidine also gave only a complex mixture from which none of the expected
piperidine derivatives (124) or (125) could be isolated.
Despite the failure to obtain the pure isocyanide dibromide (11 6a) it was decided to
attempt (Scheme 32) the Lewis acid cydlisation of the isocyanide dihalide mixture
(1 16a and b) and (I 17a - c). It was again hoped that the expected mixture of
halobenzonapthoxazepines (1 18a and b) and (119 a and b) would be more readily
separated into the individual components.
The mixture of isocyanide dihalide compounds was therefore treated with aluminium
tribromide (Scheme 32) in dichloromethane at room temperature. This reaction
afforded a brown solid whose t.l.c in a variety of solvent systems indicated it to be a
close running two component mixture which was inseparable by flash
chromatography. However the mass spectrum of the product mixture showed the
presence of mainly the bromobenzonaphthoxazepine (1 18a), the
chlorobenzonaphthoxazepine 0 18b), a dibromobenzonaphthoxazepine 0 19a), and a
Hal
16 +
I Hal'
1a1 2
(118) Hal'
(119)
Hal' Hal' Br a;
Br Br
Cl
b;
Cl Br
1(i) or (ii)
H 101
H
+
r
(126)
(127)
AcOH, H20, reflux. NaOEt, EtOH, reflux.
Scheme 36
83
chlorobromobenzonaphthoxazepine (1 19b). From the previous investigation of the
position of the chioro substituent in the isocyanide dlhalide (1 16b) and the isocyanide
trihalide (11Th or c) it was believed that the chioro group was not substituted on the
naphthalene ring system. Thus simplification of the mixture (118a and b) and (1 19a
and b) by displacing the halo compound on the diazepine ring would give only two
products. An attempt was therefore made to react (Scheme 36) the mixture of halo
compounds (1 18a and b) and (1 19a and b) with aqueous acetic acid under reflux. It
was hoped that this reaction would give a separable mixture of the
benzonaphthoxazepinone derivatives (126) and (127). In practice the mixture
obtained could not be separated into identifiable products. However the mass
spectrum indicated the presence of only the naphthobenzoxazepinone (126) and a
bromo derivative (127). This result confirms that the original mixture contains only
the chloro substituent in the diazepine ring rather than the naphthalene ring system.
In a further attempt to verify the position of the chloro substituent the mixture of
naphthodiazepines (11 8a and b) and (11 9a and b) was treated with sodium ethoxide
in ethanol at room temperature. This reaction afforded a solid product mixture whose
mass spectrum showed its main components to be the naphthobenzoxazepinone (126)
and its bromo derivative (127). Again unfortunately separation of this mixture
proved unsuccessful. However the formation of only the two benzonaphth
oxazepinones (126) and (127) by hydrolysis of the halobenzonaphthoxazepine mixture
verifies the composition of the latter. Thus formation of the unhalogenated
84
benzonaphthoxazepinone (126) is consistent with the presence of the
halobenzonaphthoxazepines (11 8a and b). Correspondingly formation of the
bromobenzonaphthoxazepinone (127) is explicable by the presence of naphthalene
ring - brominated compounds (119a and b). It follows that the chlorine atom in the
compound (11 7b) must be sited in the oxazepine ring rather than the naphthalene ring.
At this stage, with evidence that the Lewis acid catalysed cydlisation had occurred, it
was decided to seek other conditions for the specific synthesis of the isocyanide
dibromide (1 16a). Since the source of the chlorine in the isocyanide dlhalides (1 16b),
(1 17b) and (1 17c), could only be the dichioromethane used as reaction solvent or
more plausibly traces of hydrochloric acid therein, it was decided to repeat the
reaction of the isocyanide (115) with bromine in ether at -78°. This reaction gave an
excellent yield (100%) of the required isocyanide dibromide derivative (11 6a). The
mass spectrum of this unstable product was entirely consistent with its assigned
structure. Significantly there was no evidence for the formation of the isocyanide
bromochloride (1 16b), a bromo-isocyanide dibromide (1 17a), a bromo-isocyanide
bromochioride (11Th) or a bromo-isocuanide dichloride(1 llc).
With the isocyanide dibromide derivative (1 16a) in hand its cyclisation to the
benzonaphthoxazepine (1 18a) was next investigated. Since, previously,
dichioromethane had apparently become involved in the reaction of the isocyanide
derivative (115) with bromine it was decided to attempt the Lewis acid catalysed
85
cyclisation reaction of the isocyanide dibromide derivative (1 16a) using a non-
chlorinated solvent. Initially ether was chosen as a suitable solvent. Unfortunately it
was found that ether appeared to react with the aluminium tribromide which it was
intended to use as the Lewis acid catalyst. At this point it was decided to switch to
tetrahydrofliran as the reaction solvent. Thus the isocyanide derivative (115) was
reacted with bromine in tetrahydrofuran at -10 °C and gave the isocyanide dibromide
(11 6a) in a quantitative yield. Unfortunately however aluminium tribromide was
again found to react with tetrahydrofuran thus precluding its use in the Lewis acid
catalysed cyclisation.
In view of the difficulty of obtaining a solvent other than dichloromethane which
would be compatible with aluminium tribromide it was decided to investigate the
Lewis acid catalysed cydlisation of the isocyanide dibromide (1 16a) in
dichloromethane. It was hoped that in contrast to the chlorination which occurred
when this solvent was used in the attempted synthesis of the isocyanide dibromide
(1 16a) its use in the Lewis acid catalysed cyclisation of the latter would not be
similarly complicated. The isocyanide dibromide (11 6a) was therefore reacted with
aluminium tribromide in dichloromethane at room temperature. Unfortunately
however this reaction yielded only a complex mixture the mass spectrum of which
showed the presence of the benzonaphthoxazepinone (126) and its bromo derivative
(127), the bromobenzonaphthoxazepine (11 8a), the chlorobenzonaphthoxazepine
(1 18b), a dibromobenzonaphthoxazepine (1 19a) and a dichlorobenzonaphthoxazepine
86
(1 19c). The presence of the dichlorobenzonaphthoxazepine (1 19c) was entirely
unexpected as this suggested the naphthalene ring had been substituted with chlorine.
It was considered at this stage that the chlorination of the naphthalene ring had
occurred through an intermediate involving the Lewis acid and the displaced halogen
atom. Due to the complex nature of the mixture it was not further investigated.
Since ether solvents reacted with the Lewis acid catalyst it was decided to use the
bromine containing solvent dibromomethane as an alternative. However it was
recognised that the use of this solvent might lead to bromination of the naphthalene
ring. The isocyanide (115) was therefore treated with bromine in dibromomethane at
-10°C to give a product whose high resolution mass spectrum confirmed it to be a
bromo-isocyanide dibromide (11 7a).
Having successfully obtained a single bromo-isocyanide dibromide derivative (11 7a)
its cyclisation to the corresponding benzonaphthoxazepine derivative (1 19a) was next
investigated. The bromo-isocyanide dibromide (11 7a) was therefore treated at room
temperature with aluminium tribromide in dibromomethane. Unfortunately this
reaction yielded only a series of intractable gums with no evidence for the formation
of the desired cyclic product (1 19a).
In view of the apparent involvement of the solvent in the halogenation of the
isocyanide derivative (115) to give an inseparable mixture of haloisocyanide
87
derivatives it was decided to investigate in a blank experiment whether the solvent on
its own could halogenate the isocyanide derivative (115). However dissolution of the
isocyanide (115) in dibromometbane followed by rotary evaporation yielded only the
starting isocyanide derivative (115). This result indicates that dibromomethane on its
own cannot directly brominate the isocyanide derivative (115).
Since dibromomethane has a relatively high boiling point it is difficult to remove after
reaction. It was therefore decided to attempt to brominate the iso cyanide dibromide
(11 6a) in ether to give the bromo-isocyanide dibromide (11 7a). Thus the isocyanide
dibromide (1 16a) was dissolved in ether and treated with bromine at -78 °C.
Unfortunately this reaction afforded a mixture whose mass spectrum indicated the
presence of both the isocyanide dibromide (1 16a) and the bromo-isocyanide
dibromide (1 17a).
At this stage it was decided to make a final attempt to effect the Lewis acid catalysed
cyclisation of the bromo-isocyanide dibromide (1 17a). The latter compound was
therefore treated with aluminium tribromide in dichioromethane at room temperature.
Unfortunately this reaction yielded a complex mixture whose mass spectrum
indicated the presence of the bromonaphthoxazepine (11 8a), the chlorobenzo
naphthoxazepine (11 8b), a dibromobenzonaphthoxazepine (11 9a) and a
bromochlorbenzonaphthoxazepine (11 9b). The presence of the chlorinated products
(1 18b) and (1 19b) in the mixture implies that somehow dichloromethane or possibly
(j)
OH
OH
(111)
(i) PhCH2NMe3Br3 or Bu4NBr3 , MeOH, CH202, room temp.
Scheme 37
88
traces of hydrochloric acid in the latter has become involved in the reaction. The
chioro structures assigned to the products (1 18b) and (1 19b) are based on the
likelihood that chlorination under the particular reaction conditions involved occurs at
the naphthalene ring.
In parallel with the above studies it was decided to investigate if the site of bromo
substitution on the naphthalene ring could be blocked. It was believed that the 4-
position on the naphthalene ring was the most likely site of the halogenation. Thus to
prevent unwanted bromination of this site it was decided to block the 4 -position with
bromine before the bromination of the isocyanide derivative. The successful
bromination of the 4 -position would therefore prevent unwanted bromination and
thus inseparable mixtures when the bromination and subsequent Lewis acid cydlisation
was attempted. From the literature 141 451 it was found that benzyltrimethyl-
animonium perbromide could selectively brominate the para position of phenols.
Thus it was decided to investigate the possibility of using benzyltrimethylammonium
perbromide to brominate the 4-position of 1-naphthol (111). The synthesis of
benzyltrimethylammonium perbromide proceeded as described in the literature. Thus
the reaction (Scheme 37) of l-naphthol (111) with benzyltrimethylammonium
perbromide in methanol and dichloromethane was attempted. Unfortunately this
reaction yielded an unresolvable mixture which could not be separated.
(112)
I1
N—CHO cj Br
NO2 N Br
(i)
\/
(129)
1(i) or (ii)
(iv)
2 NH Br
(I3 1 )
(130) S.
S. S.
.5 S.
cL N Br
(132)
Br2, CH202 , reflux. SnC12 ,THF, HC1, reflux. H2, Ra-Ni, AcOH, room temp. HCO2H, reflux.
Scheme 38
E3
A second attempt to block the site on the naphthalene ring that was believed to be
brominated during the bromination of the isocyanide (115) was made. It was decided
to attempt to broniinate the previously synthesised 1 -(2-nitrophenoxy)naphthalene
(112). In the hope that this would eventually lead to the bromo-isocyanide (132). The
first step of the synthesis (Scheme 38) of the bromoisocyanide derivative (13 2) was
the reaction of the nitro derivative (112) with bromine in dichioromethane under
reflux. This reaction afforded a product, in excellent yield (90%), which analysed
correctly and gave mass, i.r. and 'H n.m.r. spectra consistent with the bromo-nitro
derivative (129).
Reduction of the bromo-nitro compound (129) using stannous chloride in aqueous
tetrahydrofuran in the presence of hydrochloric acid gave a two component mixture
which proved to be unresolvable. A further attempt to reduce the bromo-nitro
derivative (129) was made using Raney nickel catalyst. Reduction of the bromo-nitro
compound (129) in acetic acid using hydrogen over Raney nickel catalyst again gave a
two component mixture. The mass spectrum of this two component mixture showed
it to contain the 1-(2-aminophenoxy)naphthalene (113) and the desired 1-(2-
aminophenoxy)-4-bromonaphthalene (130). Since the two component mixture was
unresolvable it was decided to proceed with the next step of the strategy i.e. the
formylation of the amine mixture. It was hoped that the corresponding formamide
mixture would be separable and that the bromo-formamide (13 1) would be obtained.
Thus the amine mixture of(1 13) and (13 0) was treated with formic acid under reflux.
CI
1- - -c—cl
(I) or (ii) or
(115)
(133)
S02C12, CH2C12 , -78°C. Br2, CH202 , -78°C, SnCL, CH202 , - 10°C. Br2, CH202, -78°C, S0202 , CH202, -78°C.
Scheme 39
KE
Unfortunately however this reaction again gave an inseparable mixture. At this stage
attempts to obtain the bromo-isocyanide (132) were terminated.
Having investigated Lewis acid catalysed cydlisation reactions of the isocyanide
dibromide (1 16a) and having been unable to isolate the desired
bromobenzonaphthoxazepine (11 8a) due to side halogenation reactions. It was next
decided to synthesise and investigated the isocyanide dichloride derivative (133).
Isocyanide dichloride derivatives also have the potential to undergo Lewis acid
cyclisation reactions. In this case it was hoped by using a chlorinated solvent that if
halogenation occurred during cyclisation then only two products would be obtained,
i.e the desired chlorobenzonaphthoxazepine (11 8b) and a chioro-
chlorobenzonaphthoxazepine (1 19c). In practice reaction of the isocyanide (115) with
sulphuryl chloride in dichioromethane at -78 0C gave only an intractable gum which
was not further investigated. Previous studies at Edinburgh 23 had shown that
dichioroisocyanides could be synthesised from isocyanide dibromides by halogen -
exchange reaction with stannic chloride. Thus the isocyanide derivative (115) was
reacted with bromine in dichloromethane at -78 °C until t.l.c indicated complete
consumption of the isocyanide derivative (115) and formation of the isocyanide
dibromide (11 6a). The reaction mixture was then treated with stannic chloride in
dichioromethane in the hope of converting the isocyanide dibromide (1 16a) into the
isocyanide dichloride (133). Unfortunately however, this reaction yielded only an
intractable gum. The attempted conversion of the isocyanide dibromide (1 16a) into
NO 2
I +
F OH
(i) p
(68)
(134)
(135)
H
F1—CH=O
0
(137)
(iv) or (v)
NC
(vi)
(138)
NaH, DMF, 100°C. H2, Pd-C, DME, room temp. HCO2H, reflux. POC13 , Pr'2NEt, CH202, room temp. C1300O2CCI3, Et3N, CH202, room temp. Br2, ether, -78°C
NH2
(136)
Br
- C - Br
co (139)
Scheme 40
91
the isocyanide dichloride (13 3) under similar conditions but using suiphuryl chloride
rather than stannic chloride as the chlorinating agent was equally unsuccessful. These
attempted halogen - exchange conditions yielded only a complex mixture which was
not further investigated.
Despite the fact that the cyclisation of the isocyanide dibromide derivative (1 16a) had
been unsuccessful it was decided in parallel with the above studies to investigate the
synthesis (Scheme 40) of isocyanide dibromide derivative( 139) and its subsequent
cyclisation.. This system was investigated as it initially involved f-naphthol in the
synthesis of the nitro derivative(135). The use of -naphthol instead of 1-naphthol led
to the potential of two bromobenzo-
naphthoxazepines products from the Lewis acid catalysed cydlisation reaction. The
potential for two final cyclic products is due to the fact that cydlisation can occur on
the benzene ring at either side of the oxygen bridge. Thus the known3 4,41 compound,
2-(2-nitrophenoxy)naphthalene (13 5) was synthesised by reaction of 2-
fluoronitrobenzene (68) with the sodium salt of f3-naphthol (134). This reaction gave
a good yield of the nitro compound (135).
Catalytic reduction of the nitro derivative (13 5) also proceeded as expected, to give
the known amine 34,45 (136) in reasonable yield (57%). The amine (136) reacted with
formic acid under reflux to give an excellent yield (93%) of the expected formamide
Oki
(137). This previously undescribed compound analysed correctly and gave mass, 'H
n.ntr., and i.r. spectra consistent with its assigned structure.
Having successfully obtained the formamide derivative (13 7) its dehydration to the
isocyanide derivative (13 8) was next investigated. Reaction of the formamide (13 7)
with phosphoryl chloride and diisopropylethylamine in dichioromethane at room
temperature gave a good yield (76%) of the required isocyanide derivative (138). The
isocyanide (13 8) analysed correctly and showed spectroscopic properties which fully
support its assigned structure. The isocyanide (13 8) was also obtained in good yield
(73%) by reaction of the formamide (137) with triphosgene in dichloromethane at
room temperature in the presence of triethylamine.
With the isocyanide derivative (13 8) readily accessible the key intermediate in the
synthetic strategy, namely the isocyanide dibromide (139), could be synthesised. In
practice reaction of the isocyanide (13 8) with bromine in ether at -78 °C gave an oil.
whose high resolution mass spectrum was fully consistent with its formulation as the
isocyanide dibromide product( 139). Due to problems encountered in attempts to
effect the acid catalysed cyclisation of the isocyanide dibromide (1 16a) (see before)
and the potential further complications involved in the cyclisation of the
dibromisocyanide (139) it was decided to terminate these investigations at this stage.
a F
N O2 c
ZPI
(68)
HO 1 1 N % )
(140)
NO2
(I) Ø
N \j
(141)
F1
N-CH=O
cLç (143) -
(144)
NaH, DMF, 100°C. SnC12, T}TF, HCl, reflux. HCO2H, reflux. POC13 , Pr' 2NEt, CH202 , room temp.
(142)
Scheme 41
93
Due to the inability to isolate the required bromobenzonaphthoxazepine (11 8a) due to
halogenation of the naphthalene ring. It was decided to investigate the effect of
changing the naphthalene system to the less reactive quinoline system in the hope that
the quinoline system was less reactive to halogenation. The reduction in reactivity of
the quinoline ring would therefore allow studies of the Lewis acid - catalysed
cyclisation reaction without the hindrance of halogenation of the ring system and the
problems encountered with the complex reaction mixtures.
Initially (Scheme 41) 8-(2-nitrophenoxy)quinoline (141) was synthesised by reaction
of 2-fluoronitrobenzene (68) with the sodium salt of 8-hydroxyquinoline (140). This
reaction gave a good yield (79%) of a product which analysed correctly and gave
mass, i.r. and 'H n.m.r spectra in accord with its identity as the required
nitrophenoxyquinoline (141). Reduction of the nitro compound (14 1) using stannous
chloride in aqueous tetrahydrofuran in the presence of hydrochloric acid gave the
amine (142) in excellent yield (8 1%). This new compound also analysed correctly and
showed mass, i.r. and 'H n.m.r spectra which confirmed its identity as the amine
(142). Reaction of the amino derivative (142) with formic acid under reflux afforded a
product, in good yield (77%), which again analysed correctly and gave mass, i.r. and
'H n.m.r spectra consistent with its formulation as the formamide (143).
The next step in the synthetic strategy was the dehydration of the formamide (143) to
give the isocyanide (144). The formamide (143) was therefore reacted with
(144)
Br
N
(i)
N/I
(145) /
/
Br ,
(146)
(i) Br2, ether, -78°C.
Scheme 42
C'N cl + HO'\
(147)
(111)
(148)
H
t1—CH=O
(150) ± -
NE:
(151)
NaH, DMF, 100°C. SnC12 , HCl, TRF, reflux. HCO2H, reflux. POC13 , P1'2NEt, CH202 , room temp.
H2
(149)
Scheme 43
94
phosphoryl chloride in dichioromethane in the presence of diisopropylethylamine at
room temperature to give an excellent yield (85%) of the isocyanide (144) whose
structure was verified by its combustion analysis and spectroscopic properties.
Having successfully obtained the isocyanide (144) its conversion (Scheme 42) into the
isocyanide dibromide (145) was next attempted. In practice reaction of the isocyanide
(144) with bromine in ether at -78°C gave a product whose high resolution mass
spectrum was entirely consistent with its identity as the expected isocyanide
dibromide derivative (145). Unfortunately due to lack of time no further work was
carried out on this system.
3.3 Studies of Lewis Acid Catalysed Cyclisation Reactions of 3-
Naphthyloxypyrid-2-ylisocvanidedibrOmides to Pyrido123-b1 naphth
I1,41oxazepines
The studies described in this section were carried out in parallel with the
investigations previously discussed in section 3.2. It was hoped in the light of the
results obtained in section 3.2 that the use of pyridine would give a system less
reactive towards halogenation and therefore less complicated than the benzene based
system. It was decided to attempt to exploit the general synthetic strategy developed
in Chapter 2 for the Lewis acid catalysed cydlisation of
naphthyloxyphenylisocyanidedihalideS. Initially it was decided to further investigate
the potential of the novel Lewis acid catalysed heterocyclisation reactions of suitable
•1--N:C
(151)
Br Br
N N*
Br
+
(152)
(153)
r1I
Hal l
+
6F
(154)
(155)
Hal'
Hal2 Br
Br Cl
Br
Br2, solvent, -78°C. A113r3 , solvent, room temp or reflux.
Scheme 44
isocyanide dihalides for the general synthesis of pyrido[2,3,-b]naphth[1,4]oxazepines.
The proposed synthesis (Schemes 43 and 44) involved the initial formation of the
nitropyridyloxynaphthalene (148). This compound was prepared by reaction of 2-
chloro-3 -nitropyridine (147) with the sodium salt of 1-naphthol (I 11) in
dimethylformaniide at 100°C. This reaction afforded a product in good yield (85%)
which analysed correctly and had mass, i.r and 'H n.m.r. spectra in accord with its
identity as the expected 1-(3-nitropyrid-2-yloxy)naphthalene (148).
Reduction of the nitropyridyloxynaphthalene (148) using stannous chloride in aqueous
tetrahydrofuran in the presence of hydrochloric acid gave the amine (149) in excellent
yield (91 %). Reaction of the aminopyridyloxynaphthalene (149) with formic acid
under reflux afforded a product in reasonable yield (67%) whose combustion analysis,
mass, i.r and 'H n.m.r. spectra showed it to be the expected formamide (150). The
formamide derivative (150) reacted as expected with phosphoryl chloride in
dichioromethane in the presence of diisopropylethylamine at room temperature to give
a good yield (73%) of the expected isocyanide (15 1) identified by its combustion
analysis and spectroscopic properties.
Having successfully obtained the isocyanide (15 1) its conversion (Scheme 44) into the
isocyanide dibromide (152) was next attempted. Thus the isocyanide (15 1) was
reacted with bromine in dichioromethane at -78°C. This reaction yielded a solid which
was shown to be an inseparable two component mixture. The mass spectrum of the
mixture showed it to contain a isocyanide dibromide derivative (152) and a bromo-
isocyanide dibromide (153). In contrast to this reaction treatment of the iso cyanide
(152) with bromine in ether at -78°C gave a single product, in quantitative yield,
whose i.r and high resolution mass spectra confirmed its identity as the isocyanide
dibromide derivative (152)
Having successfully obtained the isocyanide dibromide (152) its cyclisation to the
bromopyridonaphthoxazepine (1 54a) was next investigated. It was decided to
investigate the Lewis acid catalysed cyclisation reaction of the isocyanide dibromide
(152) in tetrahydrofuran. Initially tetrahydrofuran was chosen as a suitable solvent
because previously in section 3.2 dichloromethane was found to get involved in the
reaction. Unfortunately as in the case of ether the Lewis acid, aluminium tribromide,
was found to react with the tetrahydrofuran thus precluding its use as the reaction
solvent.
Due to the apparent involvement of dichloromethane during the bromination reactions
in section 3.2 it was decided therefore to attempt the Lewis acid catalysed cyclisation
of the isocyanide dibromide derivative (152) using dibromomethane as the solvent in
the expectation that any involvement of this solvent would result in only two products
namely a bromopyridonaphthoxazepine (1 54a) and a di-bromopyridonaphtboxazepine
(155a) thus simplifying the subsequent product separation and identification. Before
attempting the Lewis acid catalysed cyclisation the isocyanide dibromide derivative
97
(152) was dissolved in dibromomethane and the solution monitored to exclude any
bromination by the solvent. No reaction was observed and therefore the reaction
solution was treated with aluminium tribromide at room temperature. Unfortunately
this reaction yielded a complex mixture whose mass spectrum indicated the formation
of the desired bromopyridonaphthoxazepine (1 54a), a dibromopyridonaphthoxazepine
(155a), the pyridonaphthoxazepinone (156) and its bromo derivative (157). From the
above result the solvent, dibromomethane, somehow becomes involved in the Lewis
acid catalysed cyclisation reaction of the isocyanide dibromide derivative (152). Or
perhaps the isocyanide dibromide becomes a brominating agent, another possibility is
that the Lewis acid perhaps forms a complex with the displaced bromine which in turn
brominates the bromopyridonaphthoxazepine (154) to give a bromo-bromopyrido-
naphthoxazepine (1 55a).
It was next decided to investigate the Lewis acid catalysed cyclisation of the
isocyanide dibromide derivative (152) using dichloromethane as the reaction solvent.
However, it was first decided to establish whether the reaction solvent, in this case
dichioromethane, could become involved in halogen exchange or substitution with the
starting isocyanide dibromide derivative (152). Thus the isocyanide dibromide (152)
was dissolved in dichloromethane and monitored by t.l.c for any reaction. No
evidence of halogen exchange or substitution of the isocyanide dibromide (152) was
obtained. It was therefore decided to attempt the Lewis acid catalysed cyclisation
Br Hal l
N 16 +
N*T laI2
(154)
(155)
Hall Ha!2 Br Br Cl Br
H N
Xe
H N
IC
~
(156) (157)
(i) AcOH, H20, reflux.
Scheme 45
N
N
(159)
JS) --
. 5k, (158)
Br
Hal l
+
(_~N, 1a12
(154)
(155)
Hal' Hal2 Br Br Cl Br
OEt
OEt
NaOEt, DMF, 100°C. Br2, CH202, reflux.
Scheme 46
98
reaction of the isocyanide dibromide derivative (152), using dichloromethane as
solvent.
Thus reaction of the isocyanide dibromide (152) with aluminium tribromide in
dichloromethane afforded a solid mixture which proved to be inseparable. The mass
spectrum of the mixture indicated the presence of the required bromopyrido
naphthoxazepine (1 54a), a dibromopyridonaphthoxazepine (1 5 5a), and a bromo
chloropyridonaphthoxazepine (155b). The formation of a chlorinated product again
indicated the involvement of the solvent during the Lewis acid catalysed cyclisation
reaction. The chloro substituent was believed to be sited on the seven membered ring
rather than the naphthalene ring. Hydrolysis studies of the mixture were carried out
to confirm the siting of the chloro substituent. It was thus decided to attempt the
conversion of the mixture of halo compounds (154a) and (155 a and b) into a mixture
of products which would be more readily separable, while at the same time clarifying
the position of the chioro substituent. The mixture of halo compounds, (154a) and
(155a and b), was therefore reacted (Scheme 45) with aqueous acetic acid under
reflux in the expectation of hydrolysing the halogen substituents on the oxazepine ring
while leaving those presumed to be in the naphthalene ring untouched. This reaction
yielded a mixture whose mass spectrum showed the presence of the
pyridonaphthoxazepinone (15 6) and a bromo - derivative (157). This result verifies
that the chioro substituent in the bromochloropyridonaphthoxazepine (15 Sb) is in the
reactive position of the oxazepine ring. Conversely the bromo substituent is probably
N:2
(148)
N—CH=O
Br
(162)
NO2 N Br
, q.0 (i)
1(u) NH 2
N Br
(iv) or
or (vi)
NE: Br
Br2, CH2C12, -78°C. SnC12, HCl, THF, reflux. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp. Pb3P, CC14, Et3N, C1(CH2)2C1. 60°C. C1300O2COC13, Et3N, CH202, reflux.
Scheme 47
on the naphthalene ring, bromination of the latter being more likely than bromination
of the less reactive pyridine ring.
Unfortunately the hydrolysis mixture proved inseparable. In an alternative attempt to
convert the mixture of halo compounds (154a) and (155 a and b) into a separable
product mixture (Scheme 46) it was reacted with ethanolic sodium ethoxide under
reflux in the hope that the expected mixture of ether products (158) and (159) would
be more readily separated. In practice the mass spectrum of the two component
mixture obtained did indeed demonstrate the presence of only the two ether products
(15 8) and (159). Again however these proved inseparable by flash chromatography.
An attempt to completely brominate the mixture of (15 8) and (159) to give entirely
the latter, by heating with bromine in dichloromethane under reflux, was unsuccessful.
Having had limited success in the Lewis catalysed cyclisation reactions of the
isocyanide dibromide (152) it was decided to attempt to synthesise the bromo-
isocyanide dibromide (153). It was hoped that Lewis acid catalysed cyclisation of this
compound (153) would give a mixture which, would, on hydrolysis give a single
product. Reaction of the isocyanide dibromide (152) with bromine in dibromomethane
afforded a product which analysed correctly and gave mass, i.r. and 'H n.m.r. spectra
in accord with its formulation as the bromo-isocyanide dibromide (153). It was
decided to repeat the reaction in dichioromethane to see if chlorination occurred and
also for ease of removal of the lower boiling solvent. Thus repetition of the above
100
reaction but using dichioromethane as solvent yielded a mixture whose mass spectrum
indicated the presence of unreacted starting isocyanide dibromide (152) and the
bromo-isocyanide dibromide (153).
As with the previously discussed phenoxynaphthalene system in section 3.2 it was
decided to investigate (Scheme 47) the bromination of the nitro derivative (148) at the
4 - position. The first step of the synthesis of the bromo-isocyanide derivative (163)
was the reaction of the nitro derivative (148) with bromine in dichioromethane under
reflux. This reaction afforded a product in excellent yield (99%) which analysed
correctly and gave mass, i.r and 'H n.m.r. spectra consistent with the expected 1-
bromo-4-(3-nitropyrid-2-yloxy)naphthalefle (160).
Reduction of the bromo-nitropyridyloxynaphthalene (160) using stannous chloride in
aqueous tetrahydrofuran in the presence of hydrochloric acid gave the amine (161) in
moderate yield (67%) which in turn reacted as expected with formic acid under reflux
to give a good yield (78%) of the expected formamide derivative (162).
The next step in the synthesis was the dehydration of the formamide (162) to give the
isocyanide (163). However reaction of the formamide (162) with phosphoryl chloride
in dichioromethane at room temperature in the presence of diisopropylethylamine
under standard conditions yielded only unreacted starting material. The alternative
formation of the isocyanide (163) by reaction of the formamide (162) with carbon
+ - NC
Br
N Os&
(163)
Br
(i) N
(IN 0
Br I/>
(153)
Hall
N=Ka F Ia12
Br2, solvent, -78°C. AIBr3, CH202, reflux.
(155) Hal' Hal2 Br Br Cl Br
Scheme 48
N
(165) (lm)
+- N:C
(151)
I(i) Iw
N*
(164)
IOi)
+
S0202 , solvent, -78°C. AIC13 , solvent, room temp or reflux.
Scheme 49
101
tetrachloride and triphenyiphosphine in 1 ,2-dichloroethane in the presence of
triethylamine was more successful. This reaction afforded a product in low yield
(43%) whose analytical and spectroscopic properties were consistent with it being the
isocyanide (163). In a further attempt to improve the yield of the latter (163) the
formamide (162) was treated with triphosgene and triethylamine in 1,2-
dichioroethane. Unfortunately this reaction also did not proceed efficiently yielding
the isocyanide (163) only in low yield.
Having successfully obtained the isocyanide derivative (163) its conversion (Scheme
48) into the bromo-isocyanide dibromide (153) was next attempted. Thus the
isocyanide (163) was reacted with bromine in ether at -78°C. This reaction afforded a
product whose melting point, i.r and mass spectra were consistent indicated it to be
the required bromo-isocyanide dibromide (153).
With the bromo-isocyanide dibromide (15 3) readily available the key step of the
synthesis, namely its Lewis acid catalysed cydlisation, could now be attempted.
Unfortunately reaction of the bromo-isocyanide dibromide (153) with aluminium
tribromide in dichioromethane under reflux yielded a two component mixture, whose
preparation proved impossible. The mass spectrum of the mixture indicated the
presence of the dibromopyridonaphthoxazepine (1 5 5a) and a bromochloro
pyridonaphthoxazepine (155b). Unfortunately separation of the mixture was not
possible.
ID)
Having investigated Lewis acid catalysed cyclisation reactions of the isocyanide
dibromide (152) and having been unable to isolate the desired
bromopyridonaphthoxazepine (154) due to side halogenation reactions it was next
decided to synthesise (Scheme 49) and investigate the isocyanide dichloride (164)
since isocyanide dichloride derivatives also have the potential to undergo Lewis acid
cyclisation reactions. In this case it was also hoped that by using a chlorinated solvent
that if halogenation occurred during cydlisation then only two products would be
obtained, i.e the desired chloropyridonaphthoxazepine (165) and a chloro-
chloropyridoonaphthoxazepine (166). In practice reaction of the isocyanide (15 1)
with suiphuryl chloride in ether at -78°C. The reaction afforded a product, in excellent
yield (94%), whose high resolution mass spectrum confirmed the synthesis of the
isocyanide dichloride (164). Repetition of the above reaction but in dichioromethane
also yielded only the isocyanide dichloride (164).
With the isocyanide dichloride (164) in hand its cyclisation to the
chloropyridonaphthoxazepine (165) was next investigated. Thus reaction of the
isocyanide dichloride derivative (164) with aluminium trichloride in dichioromethane
under reflux afforded a complex mixture whose mass spectrum indicated the presence
of the chloropyridonaphthoxazepine (165) and its chioro derivative (166). Repetition
of this reaction at room temperature also yielded a complex mixture whose mass
spectrum also indicated the presence of the chloropyridonaphthoxazepine (165) and
its chioro derivative (166). This result however was unexpected as chlorination of the
NO2 ~pl
NO2
aJ 0+OH N
(147) (134) (167)
H
N—CH=O
(LQ (169)
(iv) or\\\
NEC
(170)
NaH, DMF, 100°C. SnC12, HC1, THF, reflux. HCO2H, reflux. POC13 , Pr12NEt, CH2C12, room temp. Ph3P, CCU, Et3N, C1(CH2)2C1. 60°C.
Scheme 50
NH2
(168)
NEC
1(i) Br
NC — Br
Br N4
+
Br N9
(172)
(173)
Br2, solvent, -78°C. AIBr3 , C11202 , room temp.
Scheme 51
103
naphthalene ring had apparently occurred. Chlorination of the naphthalene ring had
not previously been observed in the pyridonaphthoxazepine system.
It was decided to investigate the above Lewis acid catalysed cyclisation reaction of
the isocyanide dichloride (164) using a milder Lewis acid in the hope that only the
required chloropyridonaphthoxazepine (165) would be obtained. Thus the isocyanide
dichloride derivative (164) was treated with titanium tetrachloride in dichloromethane
at room temperature. Unfortunately this reaction gave only a complex mixture.
In conjunction with the studies described previously in this section it was decided to
investigate the synthesis (Scheme 50) and cyclisation (Scheme 51) of 2-
naphthyloxypyrid-2-yl-3-isocyaiiidedibroinide(1 71). Successful Lewis acid catalysed
cyclisation of the latter could give rise to two isomeric naphthoxazepine derivatives.
The first step in the synthesis (Scheme 50) was the reaction of 2-chloro-3-
nitropyridine (147) with the sodium salt of 3-naphthol (134) in dimethylformamide at
100°C to give a good yield (82%) of the expected nitropyridyloxynaphthalene (167).
The reduction of the nitro compound (167) using stannous chloride in aqueous
tetrahydrofuran in the presence of hydrochloric acid proceeded smoothly to give the
aminopyridyloxynaphthalene (168) also in good yield (92%). The amine (168) in turn
reacted as expected with formic acid under reflux to give a good yield (77%) of the
formamide derivative (169).
NO2
NO2(I)
L LO
aNcl N OH
Br Br
(147) (174) (175)
1(ii)
H
N—CH=O NH 2
'
Br Br
(177) (176)
-F
NC
N Br
(178)
NaH, DMF, 100°C. SnC12, HCI, THF, reflux. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp.
Scheme 52
104
Reaction of the formamide derivative (169) with phosphoryl chloride in
dichioromethane at room temperature in the presence of diisopropylethylaniine gave
the isocyanide (170) though only in low yield. A further attempt to obtain the
isocyanide (170) in improved yield was made by reacting the formamide (169) with
carbon tetrachloride and triphenyiphosphine in 1 ,2-dichloroethane in the presence of
triethylamine at 60°C. These conditions gave the isocyanide (170) in slightly improved
yield (49%).
Having successfully obtained the isocyanide derivative (170) its conversion into the
isocyanide dibromide (17 1) was next attempted. Reaction of the isocyanide (170) with
bromine in ether at -78°C gave an excellent yield (93%) of the required isocyanide
dibromide (17 1) whose high resolution mass spectrum was consistent with its
assigned structure.
The Lewis acid catalysed cyclisation of the isocyanide dibromide (17 1) to the
bromopyridonaphthoxazepine (172) and (173) was next investigated. Thus freshly
prepared isocyanide dibromide (17 1) was reacted with aluminium tribromide in
dichioromethane at room temperature but unfortunately this reaction yielded only a
complex mixture with no evidence for the formation of either of the possible cyclic
products (172) or (173).
N=C
Br
IF
Br
NC — Br
Br
Br Nj
Br
Br2, solvent, -78°C. AIBr3 , CH202, room temp.
Scheme 53
Mijbi
Since cydlisation of the isocyanide dibromide (17 1) had the potential to give two
cyclic products it was next decided to investigate the synthesis and cydlisation
(Scheme 53) of 1 -bromo-2-naphthyloxypyrid-2-yl-3-isocyanidedibronhide (179). The
latter could only yield one product on cyclisation. The first step of the synthesis
(Scheme 52) of the isocyanide dibromide (179) was the reaction of 2-chloro-3-
nitropyridine (147) with the sodium salt of 1-bromo-2-naphthol (174) to give the
bromonitropyridyloxynaphthalene (1 75)in good yield.
Reduction of the nitro compound (175) under standard conditions using stannous
chloride in aqueous tetrahydrofuran in the presence of hydrochloric acid also gave the
amine (176) in excellent yield (89%) which reacted in turn with formic acid under
reflux to give a good yield (89%) of the expected formamide derivative (177).
The next step in the synthetic strategy was the dehydration of the formamide
derivative (177) to the isocyanide (178). This was accomplished in good yield (82%)
by reaction of the formaniide (177) with phosphoryl chloride in the presence of
diisopropylethylamine in dichloromethane at room temperature.
Having successfully obtained the isocyanide derivative (178) its conversion (Scheme
53) into the isocyanide dibromide (179) was next attempted. In practice the
bromination of the isocyanide (178) and subsequent Lewis acid cyclisation reaction
was carried out without isolating the iso cyanide dibromide intermediate (179).
NO2 02N N 02 (I) ao
0,)o
F) HO OH (68) (181)
(182)
CH=O O=CH I I
NH H
(ao-ao-.-O (184)
(iv) or''4%s
H 2 N H 2 N Ilk \-
II I
(183)
--I- NC CN
ao."ao'O
NaH, DMF, 100°C. H2, Pd-C, DMF, room temp, atmos. pres. HCO2H, reflux. POC13, Pr'2NEt, CH202, room temp. Ph3P, Cd 4, Et3N, C1(CH2)2C1, 60°C.
Scheme 54
106
However reaction of the isocyanide (178) with bromine in dichioromethane at -78°C
followed by heating with aluminium tribromide under reflux gave only a complex
mixture which was not further investigated.
3.4 Investigations of Lewis Acid Catalysed Cyclisation Reactions of Bis-12-
benzyloxyDhenyll isocyanidedihalides and BisI2-naphthyloxvphenvll isocyan ide
dihal ides to BenzIl51 oxazepinodibenzll.41 oxazepines and Benz[ 1.51 oxazepino
benzonaphth 11.41 oxazepines.
As a continuation of the studies described in sections 3.2 and 3.3 it was decided to
further attempt to exploit the intramolecular Friedel - Crafts type cyclisation reactions
of other types of isocyanide dibromides. As previously discussed a general synthetic
route to isocyanide dibromides and their Lewis acid catalysed cyclisation had been
developed. In this section this general synthetic route was further developed into
heterocyclic systems containing two isocyanide dibromide groups. Previously at
Edinburgh, Be W4 had synthesised (Scheme 54) the disubstituted 1,3-Di-(2-
aminophenoxy)benzene (183) and thus it was decided to use this compound to
investigate the synthesis and cyclisation (Schemes 54 and 55) of the disubstituted
isocyanide dibromide derivative (186). Synthesis of the latter initially involved the
synthesis of the diisocyanide derivative (185). This involved the reaction of 2-
fluoronitrobenzene (68) with the sodium salt of resorcinol (18 1) to give the
disubstituted nitro compound (182) in excellent yield with melting point and i.r.
spectrum comparable to those obtained by Bell34 . Catalytic reduction of the nitro
F Br Br
0
(i)
VI II II I
(185)
(186)
X(lin) Br r
OX
—0 O—b (187)
(I) Br2 , CH2C12, -78°C. (ii) AIBr3 , reflux.
Scheme 55
107
derivative (182) also proceeded as expected, in near quantitative yield, to give the
known 14 amine (183). The latter in turn reacted with formic acid under reflux to give
an excellent yield (92%) of the expected formamide (184). This previously
undescribed compound analysed correctly and showed mass, i.r. and 'H n.m.r. spectra
consistent with its assigned structure.
The next step of the synthesis was the dehydration of the formamide (184) to give the
isocyanide derivative (185). However reaction of the formamide (184) with
triphenyiphosphine and carbon tetrachloride did not proceed as expected but gave
only a complex mixture instead of the expected isocyanide (185). In a second attempt
to obtain the isocyanide (185) the formamide (184) was reacted with phosphoryl
chloride in dichloromethane at room temperature in the presence of
diisopropylethylamine under standard conditions. This reaction yielded an oil whose
mass and i.r. spectra showed it to be the required isocyanide (185).
Having successfully obtained the isocyanide derivative (185) its conversion (Scheme
55) into the isocyanide dibromide derivative (186) was next attempted. In practice it
was decided to synthesise the isocyanide dibromide (186) in situ then proceed with its
Lewis acid - catalysed cyclisation of the isocyanide dibromide (186). Disappointingly,
reaction of the isocyanide (185) with bromine in dichloromethane at -78 °C then with
aluminium tribromide under reflux did not proceed as expected and yielded only a
complex mixture which contained no material identifiable as the benzoxazepino
NO2 02N (a NO2 ,!ZIJtII1\
I + II I F OwO
HO OH
(68) (188) (189)
(ii) or (iii)
CH=O I I
NH HN
cZijCiZ:iXi (hi) or (v)atc2) 14
(191)
(190)
NC
- 4
ao 1 0
(192)
NaH, DMF, 100°C. H2 , Pd-C, DMF, room temp, atmos. pres. SnC12, HC1, THF, reflux. HCO2H, reflux. POC13 , Pr'2NEt, CH202, room temp.
Scheme 56
iiiii:
dibenzoxazepine (187).
As well as the above attempts to synthesise and investigate the Lewis acid catalysed
cyclisation of the Bis-isocyanophenoxybenzene derivative (185) the synthesis (Scheme
56) of the bis-isocyanophenoxynaphthalene (192) was studied. It was hoped that the
use of the naphthalene system would allow for easier Lewis acid - catalysed
cyclisation to the benzoxazepinobenzonaphthoxazepine. Since use of the naphthalene
system would mean that the reactions sites were further away from each other it was
hoped that this would prevent any steric problems that may have occurred with the
use of a benzene ring as the central ring in the heterocyclic system. The general
strategy for the synthesis of the required isocyanide derivative (192) followed that
already described in previous sections in this thesis. The known 14 nitro compound
(189) and amine (190) as well as the previously unknown formamide derivative (19 1)
were prepared using standard procedures. Unfortunately the formamide (191) was
not obtained in good yield and a further attempt to improve this by reaction of the
amine (190) with butylformate under reflux again gave the formamide (191 )only in
poor yield. In view of the failure to obtain the formamide (19 1) in sufficient quantities
it was decided to terminate the study of the synthesis of the diisocyano derivative
(192).
It is not clear why neither of these heterocyclic systems could be cycised perhaps in
the case of the bis-isocyanide dibromide derivative steric problems were encountered
H
NH N—CH=O
(i)
(193) (194)
CI V
C
(195)
(iv)
CI H 0
(198)
HCO2H, reflux. Ph3P, CCLI, Et3N, C1(CH2)2C1, 60°C. S0202, CH202, -10°C. ZnC12 , CH202 , reflux. Nail, 1120, DME, reflux.
Scheme 57
NO2
ZII'E' OH +
(68)
CHBr
(i)
(199)
NO2
II II I I
H
(200)
I(ii) NH
II II I IH
H
(201)
Ii' N—CH=O
II II I
H
(202)
(iv) o ' \\
ao I
H
(203)
NaH, solvent, room temp. or reflux. SnC12, HC1, T}IIF, reflux. HCO2H, HCONH2, HCO2Et, HCO2Bu", or MeCO.O.CHO, neat or solvent reflux. POC13 , Pr'2NEt, CH202, room temp. Ph3P, CCI4, Cl(CH2)2C1, 60°C.
Scheme 58
109
during the halogenation and/or cyclisation step. In the attempt to form the bis-
isocyanophenoxynaphthalene compound the further investigation and condition
optimisation is required as there appears to be no clear reason why the isocyanide
derivative could not be obtained.
3.5 Investigations of Lewis Acid Catalysed Cyclisation Reactions of Ortho-
Isocyanobenzodihalide Derivatives to Dibenzoxazocines and Dibenzodiazocines
Studies under this heading were prompted by the potential ability to exploit the
general strategy previously developed for Lewis acid catalysed cydlisation of
isocyanide dibromides. Previously, Currie 23 had successfully cydised (Scheme 57)
similar compounds to those investigated in this section.
Initially it was decided to investigate the synthesis and Lewis acid catalysed
cyclisation (Schemes 58 and 59) of the 2-Benzyloxyphenylisocyanide dibromide (204)
To this end the nitro derivative (200) and the amine (201) were synthesised under
standard conditions in good yield and had melting points comparable to those
reported in the literature '.
The attempted formylation of the amine (201) using formic acid in toluene under
reflux afforded a single product in poor yield (47%) whose analysis and mass, i.r., and
1 11 n.m.r. spectra showed it to be the expected formaniide (202). In an attempt to
improve the yield of the formamide derivative (202), the amine (201) was heated with
ac H
(203)
Br
\\ssçi )
cl
NC — Br a0 p [a0 (206)
(iv
T
Br cl
°1H
H H
(207)
Br2 , CH202 , - 10°C or -78°C. AJBr3 , CH2 C12 , -78°C. S0202, CH202 , - 10-C- ZnC12, CH202, reflux.
Scheme 59
110
formic acid in the higher boiling solvent, xylene, under reflux. These conditions
yielded the formamide (202) in slightly improved yield (56%). Reaction of the amine
with ethyl formate under reflux also afforded the desired formamide (202) in
only moderate yield (5 1%). In contrast heating the amine (201) with the higher boiling
butyl formate under reflux yielded the formamide (202) in significantly improved yield
(66%). An attempt to obtain the formamide (202) in even higher yield by heating the
amine (201) with formamide in toluene under reflux in practice gave the formamide
in only poor yield (25%). A final attempt at obtaining the formamide (202) in
high yield was made by reacting the amine (201) with formic acetic anhydride in
diethyl ether but these conditions gave only intractable material.
The next step in the synthetic strategy was the dehydration of the formamide
derivative (202) to the isocyanide (203). Reaction of the formaniide (202) with
phosphoryl chloride in the presence of diisopropylethylamine in dichloromethane at
room temperature gave a reasonable yield (50%) of the required isocyanide (203).
which gave a combustion analysis and mass, i.r. and 'H n.m.r. spectra entirely
consistent with its assigned structure. In a further attempt to obtain the isocyanide
derivative (203) in improved yield the formamide (202) was reacted with the
alternative reagent triphenylphospbine in 1 ,2-dichloroethane in the presence of
triethylamine with carbon tetrachloride at 60 °C. This reaction yielded the isocyanide
in good yield (61%).
ao I
H
(201)
(i)
r *S
II II I I
H
(208)
K qi
I H
(206)
(iii)
Xx H
ca I
H
(209)
C12=S, HC1, AcOH, room temp. C12, CHC13, -10 -C- AIC13, CH202 , room temp.
Scheme 60
III
Having successfully obtained the isocyanide derivative (203) its reaction (Scheme 59)
with bromine to give the iso cyanide dibromide (204) was next attempted. However
this reaction afforded only intractable gums with no evidence for the formation of the
isocyanide dibromide derivative (204). However repetition of the reaction of the
isocyanide derivative (203) with bromine in dichloromethane at lower temperature
(-78°C) afforded a product whose mass spectrum was consistent with it being the
required isocyanide dibromide (204). Disappointingly treatment of the isocyanide
dibromide (204) was then treated with aluminium tribromide in dichloromethane at
-78°C yielded only intractable gums with no evidence for the formation of the desired
dibenzoxazocine (205).
At this stage it was decided to attempt the synthesis (Scheme 59) of the isocyanide
dichloride (206) from the isocyanide (203) with a view to investigating its Lewis acid
catalysed cyclisation reaction. The iso cyanide derivative (203) was therefore reacted
with suiphuryl chloride in dichioromethane at -78'C then treated with zinc chloride
under reflux in an attempt to obtain the chioro-substituted dibenzoxazocine derivative
(207). Unfortunately as with the attempted Lewis acid - catalysed cyclisation of the
isocyanide dibromide (204) this reaction gave no identifiable material.
Having failed to achieve the cyclisations [(204)4(205)} and [(206)4(207)] it was
decided in passing to investigate the alternative Lewis acid - catalysed cyclisation
(Scheme 60) of the isothiocyanate derivative (208). Therefore the previously
NHMe
NO2 (i) NO2 I
CO2HCod + O (210)
(211) (212)
I(ii)
NH2 N (iii) or (iv) ziIII.:iIII
0 Me 0 Me
(213)
(v)
CH=0
(vi) c: c ,Q
0 Me 0 Me
(216)
SOCl2 , heat NaOAc, room temp. SnC12, HC1, THF, reflux. H2, Pd-C, EtOH, room temp. HCO2H, HCO2Et, HCO2Pr", HCO2Bu, or MeCO.O.CHO, neat or solvent, room temp or reflux. POCI3 , Pr'2NEt, CH202, room temp.
Scheme 61
112
prepared amine (201) was reacted with thiophosgene in acetic acid in the presence of
aqueous hydrochloric acid to give an oil in reasonable yield (58%) which gave mass,
'H n.m.r. and i.r. spectra in accord with its formulation as the isotbiocyanate (208).
However the attempted Lewis acid catalysed cyclisation of the isothiocyanate (208) to
the dibenzoxazocine derivative (209) by treatment with aluminium trichloride at room
temperature gave only a complex mixture which yielded no identifiable material.
At this stage it was decided to investigate the possibility of obtaining the isocyanide
dichloride (206) from the isothiocyanate derivative (208). However the attempted
reaction of the isothiocyanate with chlorine in dichioromethane yielded only a
complex mixture which was not further investigated.
Due to the lack of success in obtaining the dibenzoxazocine (205) or (207) it was next
decided to apply the synthetic strategy outlined in Schemes 61 and 62 to the synthesis
and cycisation of 1,1 -Dibromo- N-(benzamide- l-yl), N-methyl-phenyl
methanimine(217). 2-Nitrobenzoyl chloride (211) was readily available under
standard conditions from 2-nitobenzoic acid (210) and reacted with N-methylaniline
(212) to give the amide (213) in reasonable yield whose melting point agreed with the
literature value 411
Reduction of the nitro compound (213) using stannous chloride in aqueous
tetrahydrofuran in the presence of hydrochloric acid gave the amine (214) in poor
0 Me
(216)
y (i)
Br
NC -Br
0 Me
(217)
A' cl -Cl
0 Me
(218)
Br2, CH202, -10°C or -78°C. S02C12, CH202 , - 10-C-
Scheme 62
113
yield (22%). This product had a melting point comparable with that described in the
literature 4' as well as an i.r. spectrum fully consistent with its assigned structure. A
second attempt to obtain the amine (214) in improved yield by catalytic reduction of
the nitro compound (213) gave the desired amine (214) in excellent yield (95%). The
poor yield of the amine (214) obtained in the reduction of the nitro derivative (213)
under acidic conditions could be due to hydrolytic cleavage of the amide bond in
either the starting material (213) or the product (214). The attempted formation of
the formamide (215) by heating the amine with formic acid gave no identifiable
product. On the assumption that the failure of this reaction was due to the acidic
conditions involved it was decided to use an alternative formylating agent. However
reaction of the amine (214) with formic acetic anhydride at room temperature again
yielded no identifiable material. In a further attempt to obtain the formaniide (215),
the amine (214) was heated under reflux with ethyl formate. These conditions
afforded a good yield (80%) of a product whose analytical and spectroscopic
properties showed it to be the required formanride (215). Reaction of the amine with
propyl formate or butyl formate afforded the formamide (215) but in poorer yield than
the ethyl formate reaction.
The formamide (215) reacted, as expected, with phosphoryl chloride and
diisopropylethylamine in dichloromethane at room temperature to give a good yield
(72%) of the required isocyanide derivative (216) showed accurate mass, i.r. and
'H n.m.r. spectra consistent with its assigned structure.
0 Me
(214)
c*s
0 Me
(p" (219)
CI
NCCI
It
0 Me
HS
0 Me
(218)
(220)
C12=S, HC1, AcOH, room temp. C12, CHC13 , - 10°C. A1C13, CH202, or C1(CH2)2C1. room temp.
Scheme 63
114
Having successfully obtained the isocyanide derivative (216) its conversion (Scheme
62) into the iso cyanide dibromide (217) was next attempted. However reaction of the
isocyanide derivative (216) with bromine in dichioromethane at -10°C yielded only
intractable gums.
In an attempt to obtain the isocyanide dichloride derivative (218) for the Lewis acid
catalysed cyclisation the isocyanide derivative (216) was reacted with suiphuryl
chloride in dichloromethane at -78°C. Unfortunately this reaction again gave only a
complex mixture from which no identifiable material could be obtained.
Having failed to obtain the isocyanide dibromide derivative (217) or the isocyanide
dichloride derivative (218) it was decided in passing to investigate the alternative
Lewis acid - catalysed cyclisation (Scheme 63) of the isothiocyanate derivative (219).
Therefore the previously prepared amine (214) was reacted with thiophosgene in
acetic acid in the presence of aqueous hydrochloric acid to give a product which gave
mass, 1 H n.m.r. and i.r. spectra in accord with its formulation as the isothiocyanate
(219). However the attempted Lewis acid - catalysed cyclisation of the
isothiocyanate (219) by treatment with aluminium trichioride in dichlorometbane at
room temperature or under reflux gave only unreacted starting material. Repetition of
the above reaction but in 1,2 - dichloroethane gave only a complex mixture with no
evidence for the formation of the desired product (220).
115
At this stage it was decided to investigate the possibility of obtaining the isocyanide
dichloride, (218) from the isothiocyanate derivative (219). However the attempted
reaction of the isothiocyanate (219) with chlorine in chloroform yielded only a
complex mixture which was not further investigated.
116
3.6 Experimental
General Experimental Details.
For details of general experimental procedures see Chapter 2 section 2.4, page 34.
142-Nitrophenoxy)naphthalene (112).
A suspension of sodium hydride (5.2g ; 0.22mo1) in anhydrous dimethylformamide
(80.0ml) was stirred and treated at 0 - 10°C (ice - bath) with a solution of 1-naphthol
(I 11) (28.8g ; 0.2mol) in anhydrous dimethylformarnide (40.0m1). The suspension
was stirred at room temperature with the exclusion of atmospheric moisture for 15
min then was treated, in one portion, at room temperature with a solution of 2-
fluoronitrobenzene (68) (28.Og ; 0.2mol) in anhydrous dimethylformamide (20.0ml).
The mixture was then stirred and heated at 100°C (oil - bath) for 1 h.
The mixture was treated with water (40.Oml) and stirred at room temperature for 15
min then rotary evaporated. The residue was treated with water (800ml) and extracted
with ether (3 x 400m1) to give 1-(2-nitrophenoxy)naphthalene (112) as a pale yellow
solid (47.2g; 89%), m.p. 49 - 52°C (lit. 34, 46 - 47°C),v 1515 and 1339 (NO2) cm'
identical (imp. and i.r. spectrum) to an authentic sample.
117
142-Aminophenoxv)nanhthalene (113).
A solution of! -(2-nitrophenoxy)naphthalene (112) (42.4g ;0. 1 6mol) in 1,2-
dimethoxyethane (160m1) was hydrogenated over 10% palladium - on - charcoal
(4.2g) at room temperature and atmospheric pressure for 2.5h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
1-(2-aminophenoxy)naphthalene (113) as a brown oil (37.6g; 100%), v 3470 and
3377 (NH,) cm', identical (i.r spectrum) to an authentic sample 14
1-(2-Formamidophenoxv)naphthalene (114).
A solution of 1-(2-aminophenoxy)naphthalene (114) (35.3g; 0.15mol) in 98-100%
formic acid (300m1) was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue was washed with 10% w/v
aqueous sodium hydrogen carbonate solution then extracted with dichloromethane (3
x 150m1). Rotary evaporation of the combined dichioromethane extracts gave the
formaniide (114) (34.8g ; 93%) which formed brown crystals, m.p. 128-130°C (from
toluene - light petroleum, b.p. 80- 100°C), v 3241 (NH) and 1661 (C=O)cm', S
(CDC13) 8.85 - 8.79 (111, d, J 11.5Hz, CH), 8.53 - 8.41 (2H, m, ArH), 8.18 - 8.09
(111, m, AM), 8.01 (1H, s, NH)(exch), 7.92 - 7.87 (111, m, AM) and 7.67 - 6.78
(711, m, ArH).
118
Found: C, 77.8; H,5.2; N, 5.0% ; m/z (El ms) , 263 (M)
CHNO2 requires: C,77.6; H,4.9; N, 5.3%; M, 263.
1-(2-Isocyanophenoxy)naphthalene (115).
A solution of 1-(2-formamidophenoxy)naphthalene (114) (35.5g ; 0.14mol) in
anhydrous 1,2 dichloroethane (675m1) was stirred and treated, in one portion with
diisopropylethylamine (50.7g ; 0.41mol). The mixture was treated dropwise with
stirring at 0- 5°C (ice-salt bath) with phosphoryl chloride (23.2g; 0.15mol) and
stirred at room temperature for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution
(675m1) and stirred at room temperature for lh. The mixture was then extracted with
dichioromethane (3 x 675) to give a brown oil (35.3g) which was flash-
chromatographed over silica.
Elution with hexane-dichloromethane (3 : 2) gave a green oil which solidified on
standing to give the isocyanide (115) (25.2g ; 76%) as green crystals, m.p. 53 - 54°C,
v 2120 (NC) cm', 811 (CDC13) 8.16-8.11 (1H, m, ArH), 7.94-7.87 (111, m,
ArK), 7.73 - 7.69 (1H, d, J 8.3Hz, Aril), 7.58 - 7.40 (4H, in, ArH), 7.28 - 7.21 (111,
m, ArH), 7.11 -7.01 (2H,m, ArH), and 6.82-6.78 (111, m, ArH).
119
Found: C, 82.9; H, 4.5; N, 5.3% ; m/z (FAB ms) ,246 (Mlfl,
CH11Qreguires : C, 83.3; H,4.5; N, 5.7%; M, 245.
1Naphthy1oxvphenyI-2-isocvanidedibrOmide (116)
(a) A solution of the isocyanide (115) (0.49g ; 0.002mol) in anhydrous ether (20.Oml)
was stirred and cooled to -78°C (solid CO2 - acetone bath) then treated dropwise with
a solution of bromine (0.35g ; 0.002 mol) in anhydrous ether (20.0ml). The mixture
was stirred at -78°C, under nitrogen for lh by which time t.l.c. indicated complete
consumption of the starting material. Rotary evaporation of the mixture gave the
isocyanide dibromide (1 16a) (0.80g; 100%) as a brown oil.
Found: mlz (El FIRMS), 402.9207 (M 3)
cr NO: requires 402.9207
Found: m/z (El FIRMS), 404.9188 (M)
CH 79Br81Br NO: requires 404.9193
Found: m/z (El HRMS), 406.9169 (M)
Lir NO: requires 406.9176
A solution of the crude isocyanide dibromide (1 16a) in ether was stirred under
nitrogen and treated at room temperature with portions of a suspension of aluminium
120
tribromide (1.1 g; 0.004mol) in anhydrous ether (25 .Oml). The aluminium tribromide
was found to react with the ether and the reaction was not pursued further.
A solution of the isocyanide (115) (0.49g ; 0.002mol) in anhydrous
tetrahydrofuran (20.OmI) was stirred and cooled to -10°C (ice - acetone bath) then
treated dropwise with a solution of bromine (0.35g ; 0.002 mol) in anhydrous
tetrahydrofuran (20.0ml). The mixture was stirred at -10°C, under nitrogen for lh by
which time t.l.c. indicated complete consumption of the starting material. Rotary
evaporation of the mixture gave the isocyanide dibromide (1 16a) (0.80g; 100%) as a
brown oil. Identified by comparison (i.r. and t.l.c). with an authentic sample prepared
before.
A solution of the isocyanide (115) (0.49g ; 0.002mol) in anhydrous
dichloromethane (20.0ml) was stirred and cooled to -78°C (solid CO2 - acetone bath)
then treated dropwise with a solution of bromine (0.35g ; 0.0022 mol) in anhydrous
dichioromethane (20.0ml) and the mixture was stirred at -78°C (solid CO 2 - acetone
bath), under nitrogen for 0.5h by which time t.l.c. indicated complete consumption of
the starting material. Rotary evaporation gave a brown oil * (0.80g) whose mass
spectrum showed it to be a mixture of several halogen compounds, referred to in
further experiments as mixture of isocyanide dihalide derivatives (A)
(Table 1).
121
Table 1
Mixture Found m/z(EI ms) Formula required mass
dibromo (1 16a) 403 C 17H31 79Br2NO 403
dibromo (1 16a) 405 C171111 79Br81 BrNO 405
dibromo(116a) 407 C 1711 11 81 Br2NO 407
chlorobromo (116b) 359 C17H11 79Br35CNO 359
chiorobroino (1 16b) 361 C 171111 79Br37CINO 361
chlorobromo (1 16b) 361 C1711 11 81Br35CNO 361
chiorobromo (116b) 363 C1711 11 81 Br37CINO 363
chlorodibromo (1 17b) 437 C17H1079Br235CINO 437
chlorodibromo (1 17b) 439 C17H1079Br237CNO 439
chlorodibromo (1 17b) 439 C17H1079Br81 Br35C1NO 439
chiorodibromo (1 17b) 441 C17H1079Br81 Br37C1NO 441
chlorodibromo (11Th) 441 C17H1081 Br235CINO 441
chlorodibromo (1 17b) 443 C17H1081 Br237CNO 443
tribromo(117a) 485 C 17H1079Br3NO 485
tribromo (117a) 487 C 17H1079Br281 BrNO 487
tribromo (1 17a) 489 C17H1079Br81 Br2NO 489
tribromo (1 17a) 491 C17H1081 Br3NO 491
122
(d) A solution of isocyanide (115) (0.49g ; 0.002mol) in anhydrous dichioromethane
(10.OmI) was cooled to 0°C (ice-bath) then treated dropwise with a solution of
bromine (0.70g ; 0.0044 mol) in anhydrous dichioromethane (10.Oml). The solution
was heated under reflux for 24h,, then rotary evaporated to give a brown gum (0.75g)
whose t1c in hexane - ethyl acetate (7 : 3) showed it to be a complex mixture which
was not further investigated.
The Attempted Reaction of 1-(2-Isocyanophenoxy)naphthalene(1 15) with
Dibromomethane.
A solution of the isocyanide (115) (0.25g; 0.001mol) in anhydrous dibromomethane
(5.Oml) was stirred at -10°C (ice-salt bath) for 0.5h. The solution was rotary
evaporated and gave a green oil which solidified on standing to give unreacted
starting material (115) (0.24g; 98%), imp. 51 - 53°C, identified by comparison (imp.
and i.r spectrum) with an authentic sample prepared before.
The Attempted Synthesis of 1-(2-Isocyanophenoxv)naphthalene Dichloride (133)
(a) A solution of the isocyanide (115) (0.25g; 0.00 imol) in anhydrous
dichioromethane (10.0ml) was stirred under nitrogen and cooled to -78°C (solid CO 2
- acetone bath) then treated dropwise with a solution of sulphuryl chloride (0.14g;
0.001 mol) in anhydrous dichloromethane (10.Oml). The mixture was then stirred at
-78°C under nitrogen for 0.5h after which time t.l.c. indicated the formation of a
complex mixture which was not further investigated.
123
A solution of the isocyanide (115) (0.21g ; 0.002mol) in anhydrous
dichioromethane (5.Oml) was stirred and cooled to -78°C (solid CO 2 - acetone bath)
then treated dropwise with a solution of bromine (0.16g ; 0.00 1 mol) in anhydrous
dichloromethane (2.5m1). The mixture was then stirred at -78°C under nitrogen. for
0.5h after which time t.1.c. indicated that all the starting material had been consumed.
A solution of stannic chloride (0.26g; 0.1 2m1; 0.001 mol) in anhydrous
dichloromethane (2.5 ml) was added to the freshly prepared isocyanide dibromide
(1 16a) solution and the mixture was then stirred at -10°C (ice -salt bath), under
nitrogen, for 2h. The mixture was then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (7.5m1; 0.001mol)) and the mixture Stirred at room
temperature for 1 5mm. The mixture was filtered, to remove insoluble tin residues,
then extracted with dichloromethane (3 x 5.OmI) to give a brown gum (0.34g) whose
tic. in hexane - dichloromethane (1 1) over silica showed it to be a complex mixture
which was not further investigated.
A solution of the isocyanide (115) (0.25g ; 0.001mol) in anhydrous
dichioromethane (2.5m1) was stirred under nitrogen and cooled to -78°C (solid CO 2 -
acetone bath) then treated dropwise with a solution of bromine (0.16g ; 0.00 1 mol) in
anhydrous dichloromethane (2.5m1). The mixture was then stirred at -78°C under
nitrogen for 0.5h after which time t.Lc. indicated complete consumption of the
starting material. Rotary evaporation gave the isocyanide dibromide (1 16a) as a
124
brown oil (0.40g; 100%) identified by comparison (i.r spectrum) with an authentic
sample prepared before.
The iso cyanide dibromide (11 6a) was re-dissolved in anhydrous dichioromethane
(5.0ml) and the solution stirred under nitrogen and cooled to -78°C (solid CO 2 -
acetone bath) then treated dropwise with a solution of suiphuryl chloride (0.54g;
0.004mol) in anhydrous dichioromethane (5.0ml). The mixture was then stirred at
-78°C acetone under nitrogen for 2h.
Rotary evaporation of the mixture gave a brown gum (0.32g) whose t.l.c in hexane -
dichloromethane (1: 1) over silica showed it to be a complex mixture, (Table 2).
Table 2
Mixture Found m/z(EI ms) Formula required mass
dichloro (133) 315 C17H11 35C12NO 315
dichloro (133) 317 C 17H11 35C137C1N0 317
dichioro (133) 319 C17H11 37C12N0 319
dibromo (1 16a) 403 C17H1 1 79Br2NO 403
dibromo (1 16a) 405 C 7H11 79Br81 BrNO 405
dibromo (1 16a) 407 C17H11 81 Br2NO 407
chlorobromo (1 16b) 359 C 17H1079Br35C1NO 359
125
chiorobromo (1 16b) 361 C17H1079Br37CINO 361
chlorobromo(116b) 361 C17H1081 Br35C1NO 361
chlorobromo (1 16b) 363 C17H1081 Br37CNO 363
chlorodibromo (11Th) 437 C 17H1079Br235CINO 437
chiorodibromo (117b) 439 C 17H 1079Br237CINO 439
chiorodibromo (11Th) 439 C 17H1079Br81 Br35CNO 439
chiorodibromo (11Th) 441 C 17H1079Br81 Br37CNO 441
chiorodibromo (1 17b) 441 C 17H1081 Br235CNO 441
chiorodibromo (11Th) 443 C37H1081 Br237CNO 443
tribromo (I 17a) 485 C17H1079Br3NO 485
tribromo (1 17a) 487 C17H1079Br281 BrNO 487
tribromo (117a) 489 C17H 1079Br81Br2NO 489
tribromo (1 17a) 491 C 17H1081 Br3NO 491
The Attempted Aluminium Tribromide Catalysed Cyclisation Reactions of the
Mixture of Halogen Compounds (A).
(a) A solution of the mixture of halogen compounds (A) (2.0g; O.00Smol) in
anhydrous dichioromethane (25.0ml) was stirred, under nitrogen, and treated, with
portions of a solution of aluminium tribromide (2.8g; O.Olmol) in anhydrous
dichioromethane (20.0ml). The mixture was then stirred under nitrogen at room
temperature for 4h.
126
The dark brown solution was allowed to cool then poured into 10% w/v aqueous
sodium hydrogen carbonate solution (78.Oml; 0. imol) and the mixture stirred at room
temperature for 1 5mm. The mixture was filtered, to remove insoluble aluminium
residues, then extracted with dichioromethane (2 x 25.Oml) to give a brown solid
(4.9g) imp. 123 - 134°C which was shown by mass spectroscopy to be a complex
mixture referred to in further experiments as mixture of halogenonaphthoxazepine
derivatives (B) (Table 3)
Table 3
Mixture Found m/z(EI ms) Formula required mass
chioro (118b) 279 C17H1035C12N0 279
chioro (118b) 281 C17111037C1N0 281
bromo(118a) 323 C17H1079BrNO 323
bromo(118a) 325 C17H1081 BrNO 325
chlorobromo (1 19b or c) 357 C17H979Br81BrNO 357
chlorobromo (1 19b or c) 359 C1711981 Br2NO 359
chiorobromo (1 19b or c) 359 C 17H979Br35CINO 359
chlorobromo (1 19b or c) 361 C17H979Br37CINO 361
bromobromo (1 19a) 401 C17H979Br2NO 401
bromobromo (119a) 403 C17H979Br81 BrNO 403
bromobromo (1 19a) 405 C 17H981 Br2NO 405
127
The Attempted Aluminium Tribromide Catalysed Cyclisation of the
Bromoisocyanide Dibromide (117a
(a) A solution of the isocyanide (115) (0.49g ; 0.002mol) in anhydrous
dibromomethane (20.0ml) was stirred under nitrogen and cooled to -10°C (ice - salt
bath) then treated dropwise with a solution of bromine (0.32g ; 0.002 mol) in
anhydrous dibromomethane (5.0ml). The mixture was stirred at -10°C , under
nitrogen for 0.5h after which time t.l.c. indicated complete consumption of the
starting material. A small sample of the solution was removed for mass spectrometry
and rotary evaporated to give the crude bromoiso cyanide dibromide (11 7a) as a
brown oil;
Found: m/z (FAB HRMS), 480.8322 (MTfl.
0!NO requires : M,480.8313.
Found: m/z (FAB HRMS), 482.8278 (MFI).
C 17H 0 81 BrNO requires: M,482.8293.
Found: m/z (FAB FIRMS), 484.8282 (MIT').
co79Bf.rNO requires: M,484.8274.
Found: m/z (FAB HRMS), 486.8274 (MH').
CH1jQjqiiiiej M,486.8255.
128
The remainder of the dibromomethane solution of the bromoisocyanide dibromide
(1 17a) was stirred under nitrogen and treated at room temperature with portions of a
suspension of aluminium tribromide (1.1g; 0.004mol) in anhydrous dibromomethane
(10.Oml). The mixture was then stirred at room temperature under nitrogen for 4h.
The mixture was poured into 10% w/v aqueous sodium hydrogen carbonate solution
(32.Oml; 0.004mol) then stirred at room temperature for 15 mm. The mixture was
filtered, to remove insoluble aluminium residues, then extracted with dichioromethane
(2 x 10.Oml)to give a brown gum whose t.l.c. in hexane - ether (1:1) over silica
showed it to be a complex mixture which was not further investigated.
The Attempted Reaction of the Mixture of Isocvanisde Dihalide Derivatives (A)
with Sodium Azide.
A solution of the mixture of isocyanide dihalide derivatives (A) (0.80g; 0.002mol) in
anhydrous 1,2 - dimethoxyethane (10.Oml) was stirred and treated with portions of
sodium azide (0.13 g), over 15 min then the mixture was stirred at room temperature
with the exclusion of atmospheric moisture for 24h.
The resulting suspension was rotary evaporated to give an orange - brown residue
which was treated with water (5.Oml) then extracted with dichloromethane (3 x
5.Oml) to give a brown gum (0.74g) which was flash - chromatographed over silica
but gave no identifiable material.
129
The Attempted Reaction of the Mixture of Halo2en Compounds (A) with
Piperidine
A solution of the mixture of halogen compounds (A) (0.80g; 0.002mol) in
anhydrous dichioromethane (7.5m1) was stirred under nitrogen and cooled to 0°C
(ice - salt bath) then treated with a solution of piperidine (0.7g; 0.008mol) in
anhydrous dichioromethane (2.5ml). The mixture was then stirred at 0°C, under
nitrogen, for lh.
Rotary evaporation of the resulting solution gave a yellow - brown residue which was
treated with water then extracted with dichloromethane (3 x 10.Oml) to give a yellow
- green gum (0.79g) whose t.Lc. in hexane - ethyl acetate (1: 1) over silica showed it
to be a complex mixture which was not further investigated.
The Attempted Reaction of the Mixture of Ha1oen Compounds (A) with ortho -
phenylenediamine.
A solution of ortho-phenylenediamine (0.22g; 0.002mol) in anhydrous
dichioromethane (7.5ml) was stirred and treated, in one portion, with a solution of
triethylaniine (0.61g; 0.006mol) in anhydrous dichloromethane (2.5m1). The mixture
was then cooled to 0°C (ice - salt bath) and treated with a solution of the mixture of
halogen compounds (A) (0.80g; 0.002mol) in anhydrous dichioromethane (10.0ml).
The solution was then stirred in the melting ice bath for lh.
1I1J
Rotary evaporation of the resulting solution gave a black residue which was treated
with water (l0.Oml) and extracted with dichloromethane (3 x 1O.Oml) to give a dark
brown gum (0.68g) which was shown to be a complex mixture by t.l.c. in hexane -
ethyl acetate (1: 1) over silica, and therefore was not further investigated.
The Attempted Reaction of the Mixture of llalo2enonaphthoxazepine
Derivatives (B) with Benzvltriethvlammonium Perbromide
A solution of the isocyanide (115) (0.49g ; 0.002mol) in anhydrous dichioromethane
(20.0ml) was stirred under nitrogen and cooled to -78°C (solid CO 2 - acetone bath)
then treated dropwise with a solution of bromine (0.32g ; 0.002 mel) in anhydrous
dichloromethane (10.0ml). The mixture was stirred at -78°C under nitrogen for 0.5h
after which time t.l.c. indicated complete consumption of the starting material.
The solution was stirred under nitrogen and treated, in portions, with a solution of
aluminium tribromide (1.2g; 0.004mol) in anhydrous dichioromethane (10.Oml) at
-7 8°C under nitrogen. The mixture was then stirred at room temperature for 2h.
The mixture was poured into 10% w/v aqueous sodium hydrogen carbonate solution
(32.Oml; 0.004mol), stirred at room temperature for 15 min then filtered to remove
insoluble aluminium residues. Extracted with dichloromethane (2 x 10.Oml) to give a
brown gum (0.68g) which was dissolved in dioxane (10.Oml) then stirred and treated
with 40% aqueous benzyltriethylammonoum perbromide solution (3.4m1; 0.008mol)
then heated under reflux for 2h.
131
The mixture was rotary evaporated under high vacuum to give an orange residue that
was treated with water (1 0.Oml) then extracted with dichioromethane (2 x 10. Oml) to
give an orange - brown solid (0.37g), m.p. 132 - 139°C, whose t1c in hexane -
dichioromethane (1 : 1) over silica showed it to be a complex mixture which was not
further investigated.
The Attempted Reaction of the Mixture of Halogenonaphthoxpzepine
Derivatives (B) with piperidine.
A solution of the isocyanide (115) (1.25g ; 0.005mol) in anhydrous dichloromethane
(25.0ml) was stirred under nitrogen and cooled to -78°C (solid CO2 - acetone bath)
then treated dropwise with a solution of bromine (0.88g ; 0.0055 mol) in anhydrous
dichloromethane (25.0ml). The mixture was stirred at -78°C under nitrogen for 0.5h
after which time t.1.c. indicated complete consumption of the starting material.
The solution of the mixture of halogenonaphthoxazepine derivatives (B) was then
treated, in portions, with a solution of aluminium tribromide (2.8g; 0.01mol) in
anhydrous dichioromethane (25.0ml) at -78°C, under nitrogen and the mixture was
then stirred at room temperature for 4h.
The mixture was poured into 10% w/v aqueous sodium hydrogen carbonate solution
(80.Oml; 0.01mol), stirred at room temperature for 15 min filtered to remove insoluble
132
aluminium residues, then extracted with dichloromethane (2 x 1O.Oml) to give a
brown gum (1.6g).
The brown gum was dissolved in acetonitrile (20.0ml) and the solution stirred and
treated with a solution of piperidine(O.85g; O.Olmol) in acetonitrile then heated under
reflux, under nitrogen, for 24h.
The resulting suspension was hot filtered to give a cream solid (1.7g) m.p. 218 -
231°C whose t.l.c. in hexane - ethyl acetate (7 3) over silica showed it to be a
complex mixture which could not be separated and therefore was not further
investigated.
Rotary evaporation of the acetonitrile filtrate gave a pale yellow solid (0.53g), m.p.
145 - 187°C, whose t.l.c. in hexane - ethyl acetate over silica showed it to be a
complex mixture that could not be separated and therefore was not further
investigated.
The Attempted Reaction of the Mixture of Halogenonaphthoxazepine
Derivatives (B) with Aqueous Acetic Acid
The mixture of halogenonaphthoxazepine derivatives (B) (0.65g; 0.002mol) was
treated with 70 % aqueous acetic acid (20.0mI) then stirred and heated under reflux
for 1.5h. The resulting suspension on cooling gave a brown solid (0.089g),
133
imp. 219 - 245°C whose mass spectrum showed it to be the following mixture
(Table 4).
Table 4
Mixture Found m/z(EI ms) Formula required mass
lactam (126) 261 C17H10NO2 261
bromo(118a) 323 C17H1079BrNO 323
bromo(118a) 325 C 17H1081 BrNO 325
bromolactam (127) 339 C 17H979BrNO2 339
bromolactam (127) 341 C17H981 BrNO2 341
The Attempted Reaction of the Mixture of Haloaenonaphthoxazepine
Derivatives (B) with Sodium Ethoxide.
A solution of the mixture of halogenonaphthoxazepine derivatives (B) (0.65g;
0.002mol) in anhydrous ethanol was stirred and treated with a solution of sodium
(0.185g 0.008mol) in anhydrous ethanol (5.0ml). The suspension was stirred at room
temperature for 24h.
Rotary evaporation of the mixture gave a brown solid (0.26g) m.p. 248 - 261°C
whose mass spectrum showed it to be the following mixture (Table 5).
134
Table 5.
Mixture Found m/z(EI ins) Formula required mass
lactam (126) 261 C17H10NO2 261
bromolactam (127) 339 C17H979BrNO2 339
bromolactam (127) 341 C17H981BrNO2 341
The Attempted Reaction of the Mixture of Halo2enonaphthoxazepine
Derivatives (B) with Sodium Hydroxide.
A solution of the mixture of mixture of halogenonaphthoxazepine derivatives (B)
(0.65g; 0.002mol) in 2M aqueous sodium hydroxide (2.5 ml) and ethanol (15.0ml)
was stirred at room temperature for 24h.
The resulting suspension was filtered and the solid combined with solid material
obtained by rotary evaporating the ethanolic alkaline filtrate and treating the residue
with water (1 O.Oml) to give the unreacted mixture of halogenonaphthoxazepine
derivatives (B). (0.54g; 82%), m.p. 91 - 97°C, identified by comparison (i.r. and t.l.c.
in hexane - dichloromethane (1: 1) over silica) with an authentic sample.
135
The Attempted Catalytic Hydro2enolvsis of the Mixture of
Halogenonaphthoxazepine Derivatives (B)
A solution of the mixture of halogenonaphthoxazepine derivatives (B) (0.65g;
0.002mol) in dimethylformaniide (12.5m1) was hydrogenated over 10% palladium -on
-charcoal (0.07g) at room temperature and atmospheric pressure for A.
The mixture was filtered through ceite and the filtrate rotary evaporated under high
vacuum. The resulting residue was treated with water (10.Oml) then extracted with
dichioromethane (3 x 10.Oml) to give a brown gum (0.46g), which was flash -
chromato graphed over silica but gave no identifiable material.
Benzvltrimethvlammonium Perbromide.
Benzyltrimethylanimonium chloride (18.5g; 0.1mol) in water (50.Oml) was stirred and
treated with a solution of sodium bromide (7.6g; 0.05mol) in water (50.0ml) then the
mixture was stirred at room temperature and treated with 48% aqueous hydrogen
bromide (52.Oml; 0.3mol). The mixture was then stirred at room temperature for 0.5h.
The resulting suspension was extracted with dichioromethane (4x50.Oml) to give
benzyltrimethylammonium perbromide as an orange solid (37.2g; 95%), imp. 99 -
101°C (fit 40 100- 101°C).
136
Tetrabutvlammonium Perbromide.
Tetrabutylammonium bromide (32.2g; 0.1 mol) and sodium bromate (7.6g; 0.05mol)
were dissolved in water (200m1) and the solution was stirred and treated with a
solution of 48% aqueous hydrobromic acid (52.Oml; 0.3mol). The mixture was stirred
at room temperature for 10 min then extracted with ether (3 x 1 OOml) to give
tetrabutylammoniumperbromide as an orange solid (38.2g; 72%),m.p. 68 - 71'C.
The Attempted Synthesis of 4-Bromo-1-naphthol (128).
A solution of 1-naphthol (I 11) (7.2g; 0.05mol) in anhydrous dichioromethane
(40.0ml) and methanol (40.Oml) was stirred and treated dropwise with a solution of
benzyltrimethylammonium perbromide (19.5g; 0.05mol) in anhydrous
dichioromethane (40.Oml). The mixture was then stirred at room temperature for lh.
Rotary evaporation of the mixture gave a brown oil (14.8g) whose t.l.c in hexane -
ether (3 : 2) over silica showed it to be contain starting material. Further treatment as
before with benzyltrimethylammonium perbromide but for 22h gave no identifiable
material and the reaction was discontinued at this point.
(b) A solution of 1 -naphthol (11 1) (1.4g; 0.01mol) in anhydrous dichloromethane
(10.Oml) and methanol (10.Oml) was stirred and treated dropwise with a solution of
tetrabutylammonium perbromide (4.8g; 0.Olmol) in anhydrous dichloromethane
(5.0mI). The solution was stirred at room temperature and monitored for 6h after
which time t.l.c indicated no change and a further portion of tetrabutylammonium
137
perbromide (14.5g; 0.03mol) in anhydrous dichioromethane (15.Oml) was added and
the mixture was stirred at room temperature for a further lh.
After this period the reaction mixture was shown by t.l.c in hexane - ethyl acetate
(7 : 3) over silica to contain largely unreacted starting material. The reaction mixture
was therefore stirred and heated under reflux for 14h. After this time t.l.c. again
showed the presence of starting material and the reaction was discontinued at this
point.
4-Bromo-1-(2-Nitrophenoxy)-naphthalene (129).
The nitro compound (112) in anhydrous dichioromethane (200.0ml) was stirred and
treated at 0 - 10°C (ice-bath) with a solution of bromine (16.Og ; 0.1mol) in
anhydrous dichioromethane (50.Oml). The solution was then stirred and heated under
reflux for 24h.
The mixture was then cooled and rotary evaporated to 4-Bromo-1-(2-Nitrophenoxy)-
naphthalene (129) (31 .Og ;90%) which formed pale brown crystals, m.p. 83 - 85°C
(from ethanol), u 1531 and 1354 (NO2) cm', ô (CDC13) 8.28 - 8.16 (2H, in,
AM), 8.03 - 7.99 (1H, dd, J 8.13, 1.69Hz, AM), 7.71 - 7.46 (3H, In, AM), 7.27 -
7.19 (211, in, ArH) and 6.97 - 6.83 (2H, in, ArH).
138
Found: C, 55.8; H, 2.8; N, 3.8%; m/z (FAB ms), 344, 346 (M14)
cJHIOBrNIQ requires: C, 55.8; H, 2.9; N, 4.1%; M 343, 345.
The Attempted Synthesis of 1-(2-Aminophenoxv)-4-bromonaphthalene (130).
A solution of the nitro compound (129) (17.2g ;0.05mol) in tetrahydrofuran (500m1)
was stirred and treated with a solution of stannous chloride dihydrate (50.0g;
0.23mo1) in 2M aqueous hydrochloric acid (500m1). The mixture was then stirred and
heated under reflux for lh.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution(200m1)
and stirred at room temperature for 15 mm. concentration and extraction with ether (3
x 300m1) gave a red oil (14.5g) which was flash - chromatographed over silica, but
gave no identifiable material.
242-Nitronhenoxvinanhthalene (135).
A suspension of sodium hydride (10.4g ; 0.44mo1) in anhydrous dimethylformamide
(160.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of
- naphthol (134) (57.6g ; 0.4mol) in anhydrous dimethylformamide (80.Oml). The
suspension was stirred at room temperature with the exclusion of atmospheric
moisture for 25min then treated, in one portion, at room temperature with a solution
of 2-fluoronitrobenzene (68) (56.4g; 0.4mol) in anhydrous dimethylformamide
(40.0ml). The mixture was then stirred and heated at 100°C (oil-bath) for lh.
139
The mixture was treated with water (120.Oml) and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (800m1) and
extracted with ether (3 x 400m1) to give a brown oil which was triturated with light
petroleum - ether to give 2-(2-Nitrophenoxy)naphthalene (13 5) (60.3g ;57%) which
formed yellow crystals, m.p. 39 - 41°C (lit. 34 ' 45 39 - 40°C), u 1527 and 1358
(NO2) cm 1 .
242-Aminophenoxy)naphthalene (136).
A solution of 2-(2-nitrophenoxy)naphthalene (136) (58.3g ; 0.22 mol) in
dimethoxyethane (200m1) was hydrogenated over 10% palladium - on - charcoal
(5.8g) at room temperature and atmospheric pressure for 3.5h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
2-(2-aminophenoxy)naphthalene (13 6) (48.5g ; 94%) which formed cream crystals
m.p. 64 - 67°C (lit. 34, 45 65 - 68°C), v 3455, 3379 and 3352 (N}12) cm 1
2-(2-Formamidophenoxv)naphthalene (137).
A solution of the amine (136) (23.5g ; 0.1mol) in 98 - 100% formic acid (200.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue washed with 10% w/v aqueous
sodium hydrogen carbonate and extracted with dichloromethane (lOOml) to give the
140
formamide (13 7) (24.4g ; 93%) which formed cream crystals, m.p. 78 - 80°C (from
ethyl acetate - light petroleum), v 3251 (NH) and 1632 (C=O) cm', 8 11 (CDC13)
8.77 (1H, S, CH), 8.52 - 8.40 (111, m, ArH), 7.99 (1H, s, NH)(exch), 7.85 - 7.68
(3H, m, ArH), 7.52 - 6.72 (7H, m, ArH)
Found: C, 77.4; H, 5.2; N, 5.0%; m/z (El ms) 263 (Md),
C 1 7H13NO re C,77.6; H, 4.9; N, 5.3%; M, 263.
2-(2-Isocyanophenoxv)naphthalene (138).
(a) A solution of the formamide (137) (5.3g ; 0.02) in anhydrous dichioromethane
(100 ml) was stirred and treated, in one portion with diisopropylethylamine (7.5g;
0.06 mol). The mixture was stirred, cooled to 0 - 5°C (ice - salt bath) and treated
dropwise with phosphoryl chloride (3.4g ; 0.022 mol) then stirred at room
temperature with the exclusion of atmospheric moisture for 4h.
The deep pink mixture was treated dropwise with 1M aqueous sodium carbonate
solution (100 ml) and stirred at room temperature for I then extracted with
dichloromethane (3 x 100 ml) to give a brown oil (4.8g) which was flash
chromatographed over silica.
141
Elution with hexane - dichloromethane (1: 1) gave a green oil which solidified on
standing to give the isocyanide (13 8) (3.7g ; 76%) which formed yellow - green
crystals, imp. 54 - 55°C (from ether - light petroleum), v 2127 (NEC) cni'
(CDC13) 7.90 - 7.72 (314, m, ArH) and 7.52 - 6.95 (811, m, ArH).
Found; C, 83.2; H, 4.5; N, 5.6%; m/z (FAB ms) 246 (MIEfl,
thiNO reciuires: C,83.3; H, 4.5; N, 5.7%; M, 245.
(b) A solution of the formamide (137) (1.3g ; 0.0005 mol) in anhydrous
dichlorometbane (37.5 ml) was stirred under nitrogen and cooled to 10°C (ice - bath)
and treated dropwise with triethylamine (1 .Og ; 0.01 mol) in anhydrous
dichioromethane (6.0ml) followed by a solution of triphosgene (0.50g ; 0.00165mo1)
in dichioromethane (6.0ml). The mixture was then stirred and heated under reflux for
1.5h.
The mixture was rotary evaporated and the residue treated with water (25.0 ml) and
extracted with dichloromethane (3 x 25.Oml) to give a brown oil (1.2g) which was
flash chromatographed over silica.
Elution with hexane - dichloromethane (1: 1) gave the isocyarnde (13 8) (0.90g;
73%) as a green solid, m.p. 51 - 53°C, identified by comparison (m.p. and i.r.
spectrum) with an authentic sample prepared in (a) before.
142
2-Naphthyloxvphenyl-2-isocyanidédibromide (139).
(a) A solution of the isocyanide (13 8) (0.49g; 0.002mol) in anhydrous
dichioromethane (20.0ml) was stirred under nitrogen and cooled to -78°C (solid CO2
- acetone bath) then treated dropwise with a solution of bromine (0.35g ; 0.0022 mol)
in anhydrous dichioromethane (20.0ml). The mixture was then stirred at -78°C under
nitrogen for 0.5h after which time t.l.c. indicated that all the starting material had
been consumed. The mixture was rotary evaporated to give the isocyanide dibromide
(139) as an unstable oil (0.92g; 100%).
A sample of the isocyanide dibromide (13 9) was submitted for FAB ms, unfortunately
the sample had gone off during analysis.
Found m/z (El MS), 403 (M4)
_NO: requires 403.
Found m/z (El MS), 405 (Md).
.ciHji79Br81BrNO: requires 405.
Found: m/z (El MS), 407 (M)
j BiNO: requires 407.
143
(b) A solution of the isocyanide (138) (0.25g; 0.001mol) in anhydrous ether (10.0ml)
was stirred under nitrogen and cooled to -78°C (solid CO 2 - acetone bath) then
treated dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether
(5.Oml). The mixture was stirred at -78°C under nitrogen for 0.5h after which time
t.l.c. indicated that all the starting material had been consumed.
Rotary evaporation of the mixture gave the isocyanide dibromide (13 9) (0.92g;
100%) as a brown oil with identical i.r. spectrum with a sample prepared in (a) before.
The Attempted Aluminium Tribromide Catalysed Cyclisation of the Isocyanide
Dibromide (139).
A solution of the isocyanide dibromide (139) (2.05g; 0.005mol) in anhydrous
dichloromethane (25.Oml) was stirred under nitrogen and treated with portions of a
suspension of aluminium tribromide (2.8g; 0.01mol) in anhydrous dichioromethane
(20.0ml). The mixture was then stirred and heated under reflux for 4h.
The dark brown solution was allowed to cool then poured into 10% w/v aqueous
sodium hydrogen carbonate solution (78.Oml; 0.1mol)) and stirred at room
temperature for 1 5mm. The mixture was filtered to remove insoluble aluminium
residues, then extracted with dichloromethane (2 x 25.0ml) to give a brown oil (1.8g)
which was flash - chromatographed over silica but gave no identifiable material.
144
(b) Repetition of the reaction described in (a) before but at room temperature gave a
brown gum (1.6g) which was flash - chromatographed over silica, but again gave no
identifiable material.
842-Nitrophenoxy)guinoline (141)
A suspension of sodium hydride (4.4g ; 0.11mol) in anhydrous dimethylformamide
(30.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of
8-hydroxyquinoline (140) (14.5g ; 0.lmoI) in anhydrous dimethyllormamide (50.0m1).
The suspension was stirred at room temperature for 20min then treated, in one
portion, at room temperature with a solution of 2-fluoronitrobenzene (68) (14.1g;
0.1 mol) in anhydrous dimethylformamide (20.Oml). The mixture was then stirred and
heated at 100°C (oil-bath) for lh.
The mixture was treated with water (50.0 ml), and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (400m1) and
extracted with dichloromethane (3 x 250.Oml) to give the nitro compound (14 1)
(21.0g ;79%) which formed brown crystals, m.p. 110 - 112°C (from ethanol), u,
1517 and 1351 (NO2) cm', (CDC13 ), 8.88 (1H, dd, J 4.2, 1.7 Hz, ArH), 8.17 (111,
dd, J 8.4, 1.7, Hz, ArH), 8.04 - 7.99 (1H, dd, J 8.2, 1.7, ArH), and 7.63 - 6.94 (711,
m,ArH.
145
Found: C, 68.0; H, 3.8; N, 10.5%; m/z (FAB ms), 267 (MH)
requires : C, 67.7; H, 3.8; N, 10.5%; M 266.
842-Aminophenoxy)guinoline (142)
A solution of the nitro compound (141) (5.3g ; 0.02 mol) in tetrahydrofuran (200m1)
was stirred and treated with a solution of stannous chloride (20.Og ; 0.09 mol) in 2M
hydrochloric acid (200m1) then mixture was stirred and heated under reflux for 1 h.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (80.0ml)
and stirred at room temperature for 15 mm. The mixture was concentrated by rotary
evaporation then extracted with ether (3 x 250ml) to give the amine (142) (3.8g;
81%), which formed colourless crystals, m.p. 132 - 134°C (from toluene), Vmax 3436,
3302 and 3197 (NH) cm 1 , 8(CDC13) 8.98 (1H, dd, J4.2, 1.7 Hz, ArH), 8.16 (1H,
dd, J 8.4, 1.7 Hz, ArH) 7.94 - 6.70 (811, m, AM), and 3.84 (2H, s, N112) (exch).
Found : C, 75.7; H, 5.1; N, 11.8% ; m/z (FAB ins) , 237 (MEl)
cQrequires : C,76.3; H, 5.1; N, 11.9%; M, 236.
Found ; mlz (FAB I{RMS) 237.1046 (MW).
ç1Ji20 reufres; M, 236.1028
146
8-(2-Formamidophenoxv)uinoIine (143)
A solution of the amine (142) (8.3g ; 0.035mo1) in 98 - 100% formic acid (70.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue washed with 10% w/v aqueous
sodium hydrogen carbonate (3 x 70.0ml) then extracted with dichloromethane (3 x
140 ml) to give the formamide (143) (7.9g ; 85%), which formed colourless crystals,
m.p. 152 - 154°C (from ethanol), v 1688 (C=O) cm, H (CDC13) 9.92
(1H, br, NH) (exch), 8.51 - 8.42 (3H, m, AM and CH) 7.99 (H, d, J 8Hz, AM), and
7.44 - 6.99 (711, m, AM).
Found; C, 72.4; H, 4.6; N, 10.6%; m/z (El ms) 264 (M),
j H1 2NQ requires: C,72.7; H, 4.6; N, 10.6%; M, 264.
842-Isocyanophenoxv)ciuinoline (144)
(a) A solution of the formamide (143) (6.60g; 0.025mo1) in anhydrous 1,2 -
dichioroethane (lOOm!) was stirred and treated with carbon tetrachloride (4.5g;
0.03mol), followed by triphenylphosphine (5.0g; 0.05mol) then stirred for 15 min at
room temperature and treated with triethylaniine (5.0g; 0.05mol) then heated at 60°C
for 2.5h.
147
Rotary evaporation of the mixture gave a brown residue which was treated with water
(50.Oml) and extracted with dichlorometbane (3 x 50.Oml) to give a brown sticky
solid (11. 1 g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 3) gave the isocyanide (144) (5.2g ; 85%),
which formed colourless crystals, ntp. 144 - 146° C (from, ethyl acetate), v 2121
(NEC) cm', S (CDC1 3) 8.96 (114, dd, J 4.2, 1.7 Hz ArH), 8.20 (114, dd, J 8.7, 1.7
Hz, AM) and 7.66 - 6.89 (814, m, AM).
Found; m/z (FAB HRMS) 247.0876 (MH).
requires: M, 246.0871.
(b) A solution of formamide (143) (7.9g; 0.03mol) in anhydrous dichioromethane
(150m1) was stirred and treated, in one portion, with diisopropylethylamine (1 1.3g;
0.09moI). The mixture was stirred, cooled to 0 - 5°C (ice - salt bath) and treated
dropwise with phosphoryl chloride (5.1g; 0.033mo1) then stirred at room temperature
with the exclusion of atmospheric moisture for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution (150
ml) stirred at room temperature for I then extracted with dichloromethane (2 x
75.0ml) to give the isocyanide (144) (5.7g; 77%), identified by comparison (m.p and
i.r. spectrum) with an authentic sample prepared in (a).
148
8-Ouinyloxyphenyl-2-isocyanidedibromide (145)
A solution of the isocyanide (144) (0.24g; 0.001mol) in anhydrous ether (10.0ml)
was stirred under nitrogen and cooled to -78°C (solid CO 2 - acetone bath) then
treated dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether
(5.0ml). The mixture was stirred at -78°C under nitrogen for 0.75h after which time
t.l.c. indicated complete consumption of the starting material. The mixture was rotary
evaporated to give the isocyanide dibromide (145) (0.30 ; 75%) as an oil.
Found: m/z (El 1]IRMS),403.9160 (M)
9Br0 requires. M, 403.9160.
Found: m/z (El HRMS), 405.9133 (M*)
C19j81r0yeguires : M, 405.9141.
Found: m/z (El HRMS), 407.9126 (M)
CiBrzN0 requires : M, 407.9122.
1-(3-Nitropyrid-2-yloxv)naphthalene (148)
A suspension of sodium hydride (3.96g ; 0.1 65mo1) in anhydrous dimethlyformamide
(60.0ml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 1-naphthol
(I 11) (21.6g ; 0.15mol) in anhydrous dimethylformamide (30.0ml). The suspension
was stirred at room temperature with the exclusion of atmospheric moisture for
149
20mm. then treated in one portion at room temperature with a solution of 2-chloro-3-
nitropyridine (147) (25.4g; 0.15mol) in anhydrous dimethylformaniide (90.0ml) The
mixture was then stirred and heated at 100°C (oil-bath) for lh.
The mixture was treated with water (45.0ml) and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (600m1) and
extracted with dichioromethane (3 x 150.0ml) to give the nitro compound (148)
(34.1 g ;85%), which formed brown crystals, m.p. 129 - 131°C (from acetic acid), o
1520 and 1346 (NO2) cm 1 , [(CD3)2 SO] 8.65 (1H,dd, ArH), 8.31 (1H, dd, ArH),
8.02 (111, dd, ArH), 7.91 - 7.87 (2H, m, ArH) and 7.60 - 7.34 (5H, m, ArH).
Found: C, 67.5; H, 3.9; N, 10.5%; m/z (El ms), 266 (Mt)
C 15H10 Q3 reauires : C, 67.7; H, 3.8; N, 10.5%; M, 266.
1-(3-Aminopyrid-2-yloxv)naphthalene (149)
A solution of the nitro compound (149) (10.6g ; 0.04 mol) in tetrahydrofuran (400mi)
was stirred and treated at room temperature with a solution of stannous chloride
dihydrate (40.Og ; 0.18 mol) in 2M hydrochloric acid (400ml). The mixture was then
stirred and heated under reflux for 1 h.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (160mi)
and stirred at room temperature for 15 min. then concentrated by rotary evaporation
150
and extracted with ether (3 x 500m1) to give the amine (149) (8.6g ; 91%), which
formed pale brown crystals m.p. 135 - 137°C (from toluene), v 3436, 3304 and
3196 (NH) cm', 8 H (CDC13) 8.04 - 6.81 (1 OH, m, AM), 4.03 (2H, s, N112) (exch.).
Found: C, 76.3; H, 5.2; N, 11.6% ; m/z (El ms), 236 (M).
c1j12NQreguires : C,76.3; H, 5.1; N, 11.9%; M, 236.
1-(3-Formamidopyrid-2-yloxv)naphthalene (150).
A solution of the amine derivative (149) (14.2g ; 0.06mol) in 98 - 100% formic acid
(120.0 ml) was stirred and heated under reflux for 3K
The mixture was rotary evaporated and the residue washed with 10% w/v aqueous
sodium hydrogen carbonate and extracted with dichloromethane (3 x 60.0 ml) to give
a brown gum which was triturated with ether to give the formamide (150) (13.4g;
85%), which formed brown crystals, m.p. 123 - 125°C (from ethyl acetate -
cyclohexane), v 3369 (NH) and 1694 (C0) cm H (CDC13) 8.74 - 8.70 (211,
M AM), 8.40 (1H, d, J 1.6Hz,CHO), 8.31 (11-1, s, NH)(exch.), 7.89 - 7.71 (5H, m,
AM), 7.51 - 7.38 (3H, m, ArH), and 7.18 - 6.90 (411, m, AM).
Found C, 72.0; H, 4.5; N, 10.2%; m/z (El ms) 264 (MI 4),
requires: C,72.7; H, 4.6; N, 10.6%; M, 264.
151
1-(3-Isocyanopyrid-2-yloxy)naphthalene (151)
A solution of the formamide (15 0) (13.2g ; 0.04) in anhydrous dichioromethane
(250 ml) was stirred and treated in one portion with diisopropylethylamine
(18.8g ; 0.15 mol). The mixture was stirred, cooled to 0 - 5°C (ice - salt bath) and
treated dropwise with phosphoryl chloride (8.5g ; 0.055 mol) then stirred at room
temperature for 4h.
The deep pink mixture was treated dropwise with 1M aqueous sodium carbonate
solution (250 ml) stirred at room temperature for lh. then extracted with
dichiorometbane (3 x 250 ml) to give a brown oil which was flash chromatographed
over silica.
Elution with hexane - ethyl acetate (3: 1) gave the isocyanide (151) (8.9g ; 73%),
which formed colourless crystals, m.p. 98 - 100°C (from light petroleum - ethyl
acetate), v 2126 (NEC) cm, (CDC1 3) 8.07 - 7.77 (311, in, ArH, 7.53 - 7.24
(6H, m, ArH) and (7.04 - 6.98) (111, m, ArH).
Found; C, 78.0; H, 4.2; N, 11.3%; m/z (El ms) 246 (M),
CH10N0 requires: C,78.1; H, 4.1; N, 11.4%; M, 246.
152
1-Naphthyloxypyrid-2-yI-3-isocyanidedibromide (152)
A solution of the isocyanide (151) (2.46 g ; 0.01mol) in anhydrous
dichioromethane (50.Oml) was stirred and cooled to -78°C (solid CO2 - acetone bath)
then treated dropwise with a solution of bromine (1.6g ; 0.01 mol) in anhydrous
dichioromethane (25.0m1). The mixture was then stirred at -78°C, under nitrogen for
0.5h by which time t.l.c. indicated complete consumption of the starting material.
Rotary evaporation of the mixture gave a yellow - brown solid (1.3g) whose mass
spectrum showed it to be a mixture (Table 6).
Table 6
Mixture Found m/z (FAB ms) Formula ______________________
Required mass
dibromo (152) 405 C 1 6H1 079Br2N2O 404
dibromo (152) 407 C 1 6H1079Br81 BrNO 406
dibromo (152) 409 C16H1 081Br2N2O 408
bromodibromo (153) 483 C16H979Br3N20 482
bromodibromo (153) 485 C1 6H979Br281BrNO 484
bromodibromo (153) 487 C16H979Br81 Br2NO 486
bromodibromo (153) 489 C 1 611981 Br3N20 488
A solution of the isocyanide (151) (0.25g; 0.001mol) in anhydrous ether (10.0ml)
was stirred under nitrogen and cooled to -78°C (solid CO2 -acetone bath) then treated
dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether (5.Oml).
153
The mixture was then stirred under nitrogen at -78°C for I after which time t.l.c.
indicated complete consumption of the starting material. The mixture was then rotary
evaporated to give the isocyanide dibromide (152) (0.40g; 100%), which formed
colourless crystals, imp. 119 - 121°C, v 1663 (N=C) cm 1 .
Found: m/z (El HRMS), 403.9165 (M4).
BrjzO requires: M, 403.9160.
Found: m/z (El HRMS), 405.9154 (M4T).
c 1 79Br81 BrN20 requires: M, 405.9141.
Found: m/z (El HRMS), 407.9132 (M)
1_641 oj~B jO requires: M, 407.9122.
(c) A solution of the isocyarnde (151) (0.25g ; 0.001mol) in anhydrous
dibromomethane (10.Oml) was stirred under nitrogen and cooled to -10°C (ice - salt
bath) then treated dropwise with a solution of bromine (0.16g ; 0.001 mol) in
anhydrous dibromomethane (5.0ml). The mixture was then stirred under nitrogen at -
78°C for 0.5h after which time t.l.c. indicated complete consumption of the starting
material. The mixture was then rotary evaporated and gave a brown gum (0.43g)
whose mass spectrum indicated the presence of a mixture Table 7.
154
Table 7
Mixture Found m/z (El ms) Formula Required mass
dibromo (152) 404 C 1611 1079Br2N20 404
dibromo (152) 406 C 16H1079Br81 BrNO 406
dibromo (15 2) 408 C 16H1081 Br2N20 408
bromodibromo (153) 482 C 16H979Br3N20 482
bromodibromo (153) 484 C 36H979Br281BrNO 484
bromodibromo (153) 486 C 16H979Br81 Br2NO 486
bromodibromo (153) 486 C 16H981 Br3N20 488
Bromo-1-Naphthyloxvpyrid-2-yI-3-isocyanidedibromide (153)
(a) A solution of the isocyanide (151) (0.49g ; 0.002mol) in anhydrous
dichloromethane (20.0ml) was stirred and cooled to -78°C (solid CO 2 - acetone bath)
and treated dropwise with a solution of bromine (0.64g ; 0.004 mol) in anhydrous
dichloromethane (20.0mI). The mixture was then stirred and heated under reflux,
under nitrogen for 22h. Rotary evaporation gave the bromo-isocyanide dibromide
(153) (0.53g ; 55%), which formed colourless crystals, m.p. 130 - 131°C (from
ethanol), v 1678 (N=C) cm ' , 8 [(CD3 )2S0] 8.20 - 7.58 (611, m, ArH), and 7.48 -
7.18(411,m,ArH).
155
Found; C, 39.6; H, 2.0; N, 5.6%; mlz (FAB nis)483,485,487,489(MIfl,
Cl6HNZ0 requires: C,39.6; H, 1.9; N, 5.8%; M, 482, 484, 486, 488.
(b) A solution of isocyanide (151) (0.25g ; 0.001mol) in anhydrous ether (10.Oml)
was stirred under nitrogen and cooled to -78°C (solid CO 2 -acetone bath) then treated
dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether (5.0ml).
The mixture was then stirred under nitrogen at -78°C for 0.5h after which time t.1.c.
indicated complete consumption of the starting material. Rotary evaporation of the
mixture gave a cream solid which was dissolved in dibromomethane (10.Oml). The
mixture was stirred under nitrogen and cooled to -10°C then treated dropwise with a
solution of bromine (0.16g ; 0.001 mol) in anhydrous dibromomethane (5.0ml). The
mixture was then stirred under nitrogen at -10°C for 0.5h. Rotary evaporation of the
mixture gave an orange gum (0.44g) whose mass spectrum indicated the presence of a
mixture Table 8.
Table 8
Mixture Found m/z (FAB ma) Formula Required mass
dibromo (152) 404 C 16H1079Br2N20 404
dibromo (152) 406 C16H1079Br81 BrNO 406
dibromo (152) 408 C 1611 081Br2N20 408
bromodibromo (153) 482 C 16H979Br3N20 482
156
bromodibromo (153) 484 C 16H979Br281 BrNO 484
bromodibromo (153) 486 C16H979Br81 Br2NO 486
bromodibromo (153) 488 C16H981 Br3N20 488
(c) A solution of the isocyanide (151) (0.25g; 0.001mol) in anhydrous ether (10.0ml)
was stirred under nitrogen and cooled to -78°C (solid CO 2 -acetone bath) then treated
dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether (5.0ml).
The mixture was then stirred under nitrogen at -78°C for 0.5h after which time t.1.c.
indicated complete consumption of the starting material. Rotary evaporation of the
mixture gave a cream solid which was dissolved in dibromomethane (10.Oml). The
mixture was stirred under nitrogen and cooled to -10°C for 0.5h. Rotary evaporation
of the mixture gave an orange gum (0.44g) whose mass spectrum of the gum
indicated the presence of the isocyanide dibromide (152).
1-Naphthyloxypyrid-2-vl-3-isocyanidedichloride (164)
(a) A solution of the isocyanide (151) (0.25g ; 0.001mol) in anhydrous ether (10.0ml)
was stirred under nitrogen and cooled to -78°C (solid CO2 - acetone bath) then
treated dropwise with a solution of suiphuryl chloride (0.14g ; 0.001 mol) in
anhydrous ether (5.0ml). The mixture was then stirred at -78°C under nitrogen for
0.5h after which time t.l.c. indicated the complete consumption of the starting
157
material. Rotary evaporation gave the isocyanide dichloride (164) as a yellow oil,
(0.30g; 941/6).
Found: m/z (FAB FIRMS), 317.0253 (MIt).
C1 61111 GIN requires: M, 317.0248.
Found: m/z (El FIRMS), 319.0222 (MH)
ç 35C137CIN0 requires: M, 319.0219.
Found m/z (FAB FIRMS), 321.0188 (MIt).
SkNO reuuires : M, 321.0189.
The Attempted Aluminium Tribromide Catalysed Cyclisation of
1-Naphthyloxypyrid-2-yl-3-isocyanidedichloride (152).
(a) A solution of the isocyanide (151) (2.0 g ; 0.008mol) in anhydrous
dichioromethane (40.0ml) was stirred and cooled to -78°C (solid CO 2 - acetone bath)
then treated dropwise with a solution of bromine (1.3g ; 0.008 mol) in anhydrous
dichioromethane (20.0ml). The mixture was then stirred at -78'C, under nitrogen for
0.5h then treated, with portions of a solution of aluminium tribromide (4.48g;
0.016mol) in anhydrous dichlorometbane (40.Oml). The mixture was then stirred
under nitrogen and heated under reflux for 4h.
158
The dark brown solution was allowed to cool then poured into 10% w/v aqueous
sodium hydrogen carbonate solution (128m1; 0.1mol)) and the mixture stirred at room
temperature for 1 5mm. The mixture was filtered, to remove insoluble aluminium
residues, then extracted with dichioromethane (2 x 40.0ml) to give an orange - brown
solid which was flash chromatographed over silica.
Elution with hexane - ethyl acetate (7 3) gave a pale brown solid (1.4g), m.p. 156 -
167°C, whose mass spectrum indicated it to be a mixture, referred to in further
experiments as mixture of isocyanide dihalide derivatives (C) Table 9.
Table 9
Mixture Found m/z (El ms) Formula Required mass
bromo (1 54a) 324 C 16H979BrN20 324
bromo (154a) 326 C16H981 BrN20 326
bromo, bromo (155a) 402 C16H879Br2N20 402
bromo, bromo (155a) 404 C 16H879Br81 BrN20 404
bromo, bromo (155a) 406 C16H881 Br3N20 406
(c) Attempted repetition of the reaction described in (a) before but at room
temperature and using tetrahydrofuran as solvent resulted in the aluminium tribromide
reacting with the tetrahydrofuran and the reaction was not further investigated.
159
(d) A solution of the isocyanide (151) (0.98g ; 0.004mol) in anhydrous
tetrahydrofuran (20.0ml) was stirred and cooled to -78°C (solid CO2 - acetone bath)
then treated dropwise with a solution of bromine (0.64g ; 0.004mol) in anhydrous
tetrahydrofuran (20.0ml). The mixture was then stirred at -78°C, under nitrogen for
0.5h then rotary evaporated to give a gum (1.6g) which was dissolved in
dibromomethane (10.Oml) and treated, with portions of a solution of aluminium
tribromide (2.24g; 0.008mol) in anhydrous dibromomethane (20.0ml). The mixture
was then stirred under nitrogen at room temperature for 4h.
The brown solution was poured into 10% w/v aqueous sodium hydrogen carbonate
solution (64.0ml; 0.008mol)) and the mixture stirred at room temperature for 1 5mm.
The mixture was filtered to remove insoluble aluminium residues, then extracted with
dichlorometbane (2 x 20.0ml) to give a red oil (1.2g) whose mass spectrum showed it
to be a mixture of several halogen compounds, referred to in further experiments as
mixture of isocyanide dihalide derivatives (D) (Table 10)
Table 10
Mixture Found m/z (FAB ms) Formula Required mass
bromo (154a) 325 C1611979BrN20 324
bromo (154a) 327 C16H981 BrN20 326
bromo, bromo (155a) 403 C16H879Br2N20 402
160
bromo, bromo (155a) 405 C 16H879Br81 BrN20 404
bromo, bromo (155a) 407 C 161- 881 Br3N20 406
lactam (1 56) 263 C 16H10N202 262
bromolactam(157) 341 C 16H979BrN202 340
bromo lactam (15 7) 343 C16H981 BrN202 342
(e) Repetition of the reaction described in (d) before but using dichioromethane as the
solvent in the second step followed by the same work up gave a sticky orange solid
(0.51g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave a colourless solid (0.30g), m.p. 157 -
166°C whose mass spectrum showed it to be mixture of isocyanide dihalide
derivatives (E) (Table 11).
Table 11
Mixture Found mlz (FAB ms) Formula Required mass
bromo (154a) 325 C 16H979BrN20 324
bromo (154a) 327 C16H981BrN20 326
bromo, bromo (155a) 403 C 16H879Br2N20 402
bromo, bromo (1 55a) 405 C 1611879Br81BrN20 404
bromo, bromo (155a) 407 C 16H881 Br3N20 406
161
lactam (156) 263 C 16H10N202 262
bromo, chioro (155b) 359 C16H879Br35CIN20 358
bromo, chioro (155b) 361 C 16H879Br37CN20 360
bromo,chloro(155b) 361 C16H881 Br37CIN20 360
bromo, chioro (155b) 363 C 6H 1 Br37ClN20 362
The Attempted Reaction of the Mixture of Isocyanide Dihalide Derivatives (C)
with Auueous Acetic Acid
The mixture of isocyanide dihalide derivatives (C) (0.33g; 0.00 imol) was treated
with 70 % aqueous acetic acid (10.0ml) then stirred and heated under reflux for 0.5h.
The mixture was allowed to cool then filtered to give an orange - brown solid (0.1 g)
imp. 278 - 28 1°C whose mass spectrum showed it to be a mixture lactam derivatives.
(Table 12)
Table 12
Mixture Found m/z (FAB ms) Formula Required mass
lactam (156) 263 C16H30N202 262
bromo lactam (15 7) 341 C16H1081 BrN202 340
bromolactam(157) 343 C 1611881 BrN202 342
162
The Attempted Reaction of the Mixture of Isocyanide Dihalide Derivatives (C
with Sodium Ethoxide
The mixture of isocyanide dihalide derivatives (C) (1.3g; 0.004mol) was suspended in
anhydrous ethanol (20.0ml) then the suspension was stirred and treated with a
solution of sodium (0.37g 0.016mol) in anhydrous ethanol (10.0ml) (sodium
ethoxide). The suspension was then stirred and heated under reflux for 0.5h.
Rotary evaporation of the reaction mixture gave a brown residue which was washed
with water (20.Oml) then extracted with dichloromethane (3 x 10.Oml) to give a pale
orange solid (0.77g) imp. 109 - 112°C whose mass spectrum showed it to be a
mixture (Table 13).
Table 13
Mixture Found m/z (FAB ms) Formula Required mass
ethoxide (15 8) 291 C 181114N202 290
bromo ethoxide (159) 369 C 18111479BrN202 368
bromo ethoxide (159) 370 C 18H1481BrN202 370
The Attempted Bromination of the Mixture of Isocyanide Dihalide Derivatives
11
(a) A solution of the mixture of isocyanide dihalide derivatives (C) (0.42g;
0.0013mol) in anhydrous dichloromethane (10.Oml) was stirred under nitrogen and
163
cooled to 0°C (ice - bath) then treated dropwise with a solution of bromine (0.42g;
0.0026mo1) in anhydrous dichloromethane (5.0ml). The mixture was then stirred
under nitrogen and heated under reflux for 24h.
Rotary evaporation of the mixture gave unreacted starting material (0.42g; 100%),
identified by comparison (imp. and i.r. spectrum) with an authentic sample.
(b) A solution of the mixture of isocyanide dlhalide derivatives (C) (0.32g ; 0.001mol)
in anhydrous dichioromethane (5.0ml) was stirred under nitrogen and cooled to -78°C
(solid CO2 - acetone bath) then treated dropwise with a solution of bromine (0.16g;
0.001mol) in anhydrous dichioromethane (2.5m1). The mixture was then stirred at -
78°C, under nitrogen for 0.5h then treated, with portions of a solution of aluminium
tribromide (0.56g; 0.002mol) in anhydrous dichloromethane (5.Oml). The mixture was
then stirred under nitrogen and heated under reflux for 4h.
The orange solution was then poured into 10% w/v aqueous sodium hydrogen
carbonate solution (16.Oml; 0.002mol)) and the mixture stirred at room temperature
for 1 5mm. The mixture was filtered, to remove insoluble aluminium residues, then
extracted with dichloromethane (2 x 10.0ml) to give unreacted starting material
(0.32g; 100%), identified by comparison (imp. and i.r. spectrum) with an authentic
sample.
164
The Attempted Bromination of the Mixture of Ether derivatives (158) and (159)
A solution of the mixture of ether derivatives (158) and (159) (0.29g ; O.00lmol) in
anhydrous dichloromethane (7.5m1) was stirred and treated dropwise with a solution
of bromine (0.16g; 0.001mol) in anhydrous dichloromethane (2.5m1). The mixture
was then stirred and heated under reflux with the exclusion of atmospheric moisture
for 3h.
Rotary evaporation of the mixture gave unreacted starting material (0.20g; 69%),
identified by comparison (m.p. and i.r. spectrum) with an authentic sample. The
unreacted solid was redissolved in anhydrous dichloromethane (7.5m1) and the
solution stirred and treated with a solution of bromine (0.16g; 0.00 imol) in anhydrous
dichioromethane (2.5m1). The mixture was then stirred and heated under reflux for
19h.
Rotary evaporation of the mixture gave unreacted starting material (0.1 8g; 62%),
identified by comparison (imp. and i.r. spectrum) with an authentic sample.
The Attempted Cydlisation Reaction of 1-Naphthyloxvpyrid-2-0-3-
isocyanidedichloride (164).
(a) A solution of the isocyanide (151) (0.49g ; 0.002mol) in anhydrous
dichioromethane (10.Oml) was stirred and cooled to -78°C (solid CO2 - acetone bath)
then treated dropwise with a solution of suiphuryl chloride (0.27g ; 0.002mol) in
165
anhydrous dichioromethane (5.Oml). The mixture was then stirred at -78°C, under
nitrogen for 0.5h after which time t.l.c. indicated complete consumption of the
starting material.
The mixture was treated with portions of a solution of aluminium trichioride (0.53g;
0.004mol) in anhydrous dichioromethane (10.Oml) and the mixture was then stirred
under nitrogen and heated under reflux for 4h.
The yellow solution was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (32.Oml; 0.004mol)) and the mixture stirred at room
temperature for 1 5mm. The mixture was filtered to remove insoluble residues, then
extracted with dichloromethane (2 x 10.Oml) to give a brown gum (0.35g) whose tic.
in hexane - ethyl acetate over silica showed it to be a complex mixture which was not
further investigated.
(b) Repetition of the reaction described in (a) before but at room temperature gave a
dark brown gum (0.82g) whose t.l.c. in hexane - ethyl acetate again showed it to be a
complex mixture which was not further investigated.
The Attempted Titanium Tetrachloride Catalysed Cyclisation of 143-
Dichloroisocyanopyrid-2-yloxy)naphthalene (164).
A freshly prepared solution of the isocyanide dichloride (164) (0.63g; 0.002mol) in
dichioromethane (10.Oml) was stirred under nitrogen and cooled to -78°C (solid CO2
- acetone bath) then treated dropwise with a solution of titanium tetrachloride (0.76g;
0.46m1; 0.004mol) in anhydrous dichlorometbane (10.Oml). The mixture was allowed
to come to room temperature then stirred under nitrogen for 4h.
The mixture was poured into 10% w/v aqueous sodium hydrogen carbonate solution
(32.Oml; 0.004mol) and stirred at room temperature for 15 mm. then filtered to
remove insoluble titanium residues, then extracted with dichloromethane (2 x 10.Oml)
to give a red oil (0.44g) whose t.1.c. in hexane - ethyl acetate (7 : 3) over silica
showed it to be a complex mixture which was not further investigated.
1-Bromo-4-(3-nitropyrid-2-yloxv)naphthalene (160)
A solution of the nitro compound (148) in anhydrous dichioromethane (160m1) was
stirred and cooled to between 0 - 10°C (ice - bath) then treated with a solution of
bromine (12.8g; 0.08mol) in anhydrous dichloromethane (40.Oml) and stirred and
heated under reflux with the exclusion of atmospheric moisture for 23h.
167
Rotary evaporation of the mixture gave the bromo-nitro compound (160)
(27.2g ;99%) which formed yellow crystals, imp. 134 - 136°C (from ethanol- acetic
acid), um,,., 1519 and 1346 (NO2) cm', [(CD3) 2 SO] 8.66 (1H,dd, J 7.9, 1.7, ArH),
8.32 (1H, dd, J 4.8, 1.8, Aril), 8.22 - 8.17 (1H, m, ArH), 8.01 - 7.94 (2H, m, ArH),
7.80 - 7.60 (2H, m, ArH), and 7.43 - 7.36 (2H, in, ArH).
Found: C, 51.9; H, 2.5; N, 8.0%; m/z (FAB ms), 345, 347 (MIfl.
C15HiNzQa requires: C, 52.2; H, 2.6; N, 8.1%; M 344, 346.
1-Bromo-4-(3-aminopyrid-2-yloxv)naphthalene (161)
A solution of the nitro compound (161) (13.8g ; 0.04 mol) in tetrahydrofuran (400m1)
was stirred and treated with a solution of stannous chloride dihydrate
(40.Og ; 0.18 mol) in 2M hydrochloric acid (400ml) and the mixture was heated
under reflux for 1 h.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (160m1)
and stirred at room temperature for 15 mm. then concentrated by rotary evaporation
and extracted with ether (3 x 250m1) to give the amine (162) (8.7g ; 67%), which
formed cream crystals imp. 157 - 159°C (from acetic acid), v 3434, 3300 and
3196 (NH) cm', 8H [(CD3)2S0] 8.18 - 7.58 (5H, in, AM), 7.24 - 6.85 (4H, m, ArH),
and 5.47 (211, s, NH2) (exch.).
168
Found: C, 56.7; H, 3.4; N, 8.6% ; m/z (FAB ms), 315, 317 (MFfl.
CH requires C,57.1; H, 3.5; N, 8.9%; M 314, 316.
1-Bromo-4-(3-formamidonvrid-2-vloxv)nanhthalene (162)
A solution of the amine (161) (7.88g ; 0.025mo1) in 98 - 100% formic acid (50.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue washed with 10% w/v aqueous
sodium hydrogen carbonate (3 x 37.5m1) then extracted with dichloromethane
(25.0 ml) to give a brown oil. This on scratching gave the formamide (162)
(6.7g ; 78%), which formed pink crystals, m.p. 133 - 134.5°C (from ethyl acetate -
cyclohexane),v, 3248 (NH) and 1681 (CO) cm', 6H (CDC13) 8.78 - 8.73 (2H,
m, ArH), 8.53 (1H, s, CHO), (1H, s, NH) (exch), 7.83 - 7.72 (3H, m, ArH), 7.61 -
7.49 (2H, in, ArH), and 7.08 - 6.95 (2H, m, ArH).
Found C, 56.0; H, 3.1; N, 8.0%; m/z (FAB ms) 343, 345 (MW),
rNzQa requires: C,56.0; H, 3.2; N, 8.2%; M, 342, 344.
1Bromo-4-(3-isocvanopvrid-2-v1oxv)naPhthatefle (163)
(a) A solution of the formamide (162) (5.1g ; 0.015mol) in anhydrous
dichloromethane (75.0 ml) was stirred and treated, in one portion, with
diisopropylethylamine (5.6g ; 0.045 mol). The mixture was stirred, cooled to 0 - 5°
169
(ice - salt bath) and treated dropwise with phosphoryl chloride (2.6g ; 0.0 165 mol)
then stirred at room temperature with the exclusion of atmospheric moisture for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution
(75.0 ml) stirred at room temperature for lb then washed with water (75.0 ml).
Extraction with dichioromethane (2 x 37.5 ml) gave a brown foam which was
triturated with ether to give the starting formamide (162) (4.2g; 86%), imp. 131 -
134°C, identified by comparison (imp. and i.r.) with an authentic sample prepared
before.
(b) A solution of the formamide (162) (2.06g ; 0.006mol) in anhydrous 1,2-
dichioroethane (24.Oml) was stirred and treated with carbon tetrachloride (1.08g;
0.0072mo1) then triphenyiphosphine (1.92g ; 0.0072mo1) and the mixture was stirred
at room temperature for 15 mm. Triethylamine (1.20g ; 0.012mol) was then added
and the mixture was stirred at 60°C (oil-bath) for 2.5h.
The dark brown mixture was concentrated by rotary evaporation to remove the
dichioroethane and gave a dark brown residue which was treated with water (12.0ml)
then extracted with dichioromethane (3 x 12.Oml) to give a brown oil (3.8g) which
was flash - chromato graphed over silica.
170
Elution with hexane - ethyl acetate (4: 1) gave the isocyanide (163) (0.84g; 43%),
which formed colourless crystals, m.p. 120 - 122°C (from ethanol), v 2127 (NEC)
cm' , S (CDC13) 8.26(111, dd, J 7.6, 1.8 Hz, ArH), 8.05 (1H, dd, J4.9, 1.8 Hz,
ArH), 7.97 - 7.93 (111, in, AM), 7.84 - 7.73 (2H, in, ArH), 7.67 - 7.49 (211, in, ArH),
7.25 - 7.20 (1H, m, ArH), and (7.08 - 7.02) (1H, in, ArH).
Found: C, 58.8; H, 2.8; N, 8.6%; m/z (FAB ms) 325, 327 (MIfl,
_16HrN requires : C,59.1; H, 2.8; N, 8.6%; M, 324, 326.
(c) A solution of the formarnide (162) (1.72g; 0.005mol) in anhydrous 1,2 -
dichioroethane (37.5m1) was stirred and treated , under nitrogen, at 10°C (ice bath),
with a solution of triethylamine (1.0g; 0.01mol) in anhydrous 1,2 - dichloroethane
(6.Oml) followed by a solution of triphosgene (0.50g; 0.0017mol) in anhydrous
dichioromethane (6.Oml). The mixture was then heated under reflux for 1.5h.
Rotary evaporation gave a brown residue which was treated with water (25.0ml) and
extracted with dichloromethane (3 x 20.Oml) to give a brown solid (1.lg) whose t. Lc
in hexane - ethyl acetate (7: 3) showed it to be a complex mixture containing the
isocyanide (163) which was not further investigated.
171
The Attempted Aluminium Tribromide Catalysed Cycisation of 1-Bromo-4-
Naphthyloxypyrid-2-yl-3-isocyanidedibromide (155a)
A solution of the isocyanide (163) (0.65g) ; 0.002mol) in anhydrous dichioromethane
(10.Oml) was stirred, under nitrogen, and cooled to -78°C (solid CO 2-acetone bath)
then treated dropwise with a solution of bromine (0.35g ; 0.0022mo1) in anhydrous
dichioromethane (1O.Oml). The mixture was then stirred, under nitrogen, at -78°C for
0.5h.
The resulting mixture was treated with portions of a solution of aluminium tribromide
(1.2g; 0.002mol) in anhydrous dichioromethane (10.Oml) then stirred under reflux for
4h.
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (32.0ml; 0.004mo1)) and stirred at room temperature for
1 5mm. The mixture was filtered to remove insoluble aluminium residues, then
extracted with dichloromethane (2 x 10.Oml) to give a brown gum (0.34g) whose t.l.c
in hexane - ethyl acetate (7 3) over silica showed it to be a complex mixture which
was not further investigated.
2-(3-Nitropyrid-2-yloxv)naphthalene (167)
A suspension of sodium hydride (4.4g ; 0.11 mol) in anhydrous dimethlyformamide
(30.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of
172
3-naphthol (134) (14.4g ; 0.lmot) in anhydrous dimethylformamide (20.OmI). The
suspension was stirred at room temperature with the exclusion of atmospheric
moisture for 20mm. then treated, in one portion, at room temperature, with a solution
of 2-chloro-3-nitropyridine (147) (15.9g; 0.lmol) in anhydrous dimethylformamide
(60.Oml) and the mixture stirred and heated at 100°C (oil-bath) for lh.
The mixture was treated with water (30.0ml) and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (400m1) and
extracted with dichlorometbane (3 x 250.0ml) to give the nitro compound (167)
(21.7g ;82%), which formed yellow crystals, imp. 119 - 121°C (from ethyl acetate),
u 1517 and 1348 (NO2) cm', ô (CDC1 3 ), 8.40 - 8.29 (211, m, Ar}T), 7.94 - 7.80
(3H, m, ArH), and 7.66-7.10(511, m, ArH).
Found: C, 67.6; H, 3.9; N, 10.5%; m/z (El ms), 266 (MH4).
requires: C, 67.7; H, 3.8; N, 10.5%; M 266.
2-(3-Aminonyrid-2-yloxv)naphthalene (168
A solution of the nitro compound (167) (12.Og ; 0.045 mol) in tetrahydrofuran
(450) was stirred and treated with a solution of stannous chloride dihydrate (45.Og;
0.2025 mol) in 2M hydrochloric acid (450m1) and the mixture was heated under reflux
for lh.
173
The cooled mixture was treated with 30% w/v aqueous sodium hydroxide solution
(1 80m1) and stirred at room temperature for 15 mm. then concentrated and extracted
with ether (3 x 565m1) to give the amine (168) (9.8g ; 92%), which formed brown
crystals imp. 136 - 138°C (from ethanol), v ma,, 3449, 3345 (NH2) cm', E'H (CDC13)
7.88- 6.82 (10H, m, AM), and 3.86 (2H, s, N112) (exch).
Found; m/z (FAB ms) found 237.1038
C u Q requires: 237.1028 (MIfl
2-(3-Formamidopyrid-2-vloxv)naohthalene (169)
A solution of the amine (168) (9.44g ; 0.04mol) in 98 - 100% formic acid (80.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue washed with 10% w/v aqueous
sodium hydrogen carbonate (3 x 80.0ml) then extracted with dichioromethane (3 x
80.0 ml) to give the formaniide (169) (8.32g ; 79%), which formed brown crystals,
m.p. 108- 110°C (from toluene), v 3307 (NH) and 1688 (C=O) cm. ', 6H (CDC1 3)
8.82 (1H, in, CH), 8.75 - 6.97 (1011, in, ArH) and 2.03 (1H, s, NH) (exch)
Found C, 72.2; H, 4.6; N, 10.4%; m/z (El ms) 264 (M d),
requires: C,72.7; H, 4.6; N, 10.6%; M, 264.
174
2-(3-Isocyanonyrid-2-vloxv)nanhthalene (170)
(a) A solution of the formamide (170) (1.32g; 0.005mol) in anhydrous
dichloromethane (25.0 ml) was stirred and treated, in one portion, with
diisopropylethylamine (1 .88g; 0.01 Smol) the stirred, cooled to 0 - 5°C (ice - salt
bath) and treated dropwise with phosphoryl chloride (0.85g; 0.0055 mol) and stirred
at room temperature for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution (25.0
ml) and stirred at room temperature for lh then extracted with dichloromethane (3 x
12.5 ml) to give a brown oil (1.21g) which was flash - chromatographed over silica.
Elution with hexane - ether (7 : 3) gave the isocyanide (170) (0.42g ; 34%), which
formed colourless crystals, imp. 88 - 90°C (from cyclohexane), v 2127 (NEC) cm
oN (CDC13) 8.13 - 8.11 (1H, m, AM), 7.92 - 7.75 (411, m, Aril), 7.65 (111, d, J 4.3
Hz, ArH), 7.50 - 7.43 (214, m, ArH), 7.34 - 7.29 (1H, m, ArH) and 7.06 - 7.01 (111,
m, AM)
Found; C, 77.8; H, 4.1; N, 11.2%; m/z (El ms) 246 (Md),
]j0 requires: C,78.1; H, 4.1; N, 11.4%; M, 246.
175
Elution with hexane - ether (1: 1) gave the starting formaniide (170) (0.21g; 16%),
m.p.104 - 108°C, identified by comparison (m-p. and i.r. spectrum) with an authentic
sample prepared earlier.
(b) A solution of the formamide (169) (1.32g; 0.005mol) in anhydrous 1,2 -
dichioroethane (20.0ml) was stirred and treated with carbon tetrachloride (0.9g;
0.006mol), followed by triphenyiphosphine (1.6g; 0.006mol) then stirred at room
temperature for 15 mm. Triethylaniine (1.0g; 0.01mol) was added then the mixture
was stirred and heated at 60°C for 2.5h.
Rotary evaporation of the mixture gave a brown residue which was treated with
water (10.Oml) and extracted with dichioromethane (3 x 10.Oml) to give a brown
sticky solid (3.1 g) which was flash - chromatographed over silica.
Elution with hexane - ether (7 3) gave the isocyanide (170) (060g; 49%), m.p. 85 -
87°C, identified by comparison (m.p. and i.r. spectrum) with an authentic sample
prepared before.
2NaphthyIoxvpvrid-2-vJ-3-isocvanidCdibrOfflide (171)
A solution of the isocyanide (170) (0.24g ; 0.001mol) in anhydrous ether (10.Oml)
was stirred under nitrogen and cooled to -78°C (solid CO 2 - acetone bath) then
treated dropwise with a solution of bromine (0.16g ; 0.001 mol) in anhydrous ether
176
(5.Oml). The mixture was stirred at -78°C under nitrogen for 0.5h after which time
t.l.c. indicated complete consumption of the starting material. Rotary evaporation
gave the isocyanide dibroniide (171) (0.38 ; 93%), as an oil.
Found: m/z (El HIRMS), 403.9165 (Mt)
cj.ijio79 i2N20 requires : 403.9160.
Found: mlz (El HRMS), 405.9154 (M).
CH1079Br81BrN,O requires : 405.9141.
Found: mlz (El [IRMS), 407.9132 (M 4).
crNo requires : 407.9122.
The Attempted Aluminium Tribromide Catalysed Cydlisation of 2-
Naphthyloxvpyrid-2-vl-3-isocvanidedibromide (171)
A solution of the isocyanide (170) (0.49g) ; 0.002mol) in anhydrous dichioromethane
(10.Oml) was stirred under nitrogen and cooled to -78°C (solid CO2 -acetone bath)
then treated dropwise with a solution of bromine (0.35g ; 0.0022mo1) in anhydrous
dichioromethane (10.0ml). The mixture was then stirred at -78°C for 0.5h.
177
The mixture was treated with portions of a solution of aluminium tribromide (1.2g;
0.002mo1) in anhydrous dichioromethane (10.Oml) then stirred at room temperature
for 4K
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (32.Oml; 0.004mol)) and stirred at room temperature for
15mm. The mixture was filtered to remove insoluble aluminium residues, and
extracted with dichloromethane (2 x 10.Oml) to give a sticky brown solid (0.45g)
from which no identifiable material could be obtained.
1-Bromo-2-(3-nitroDvrid-2-vloxv)flaflhthalefle (175)
A suspension of sodium hydride (4.4g ; 0.11 mol) in anhydrous dimethylformamide
(40.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 1-bromo
2-naphthol (174)(22.3g ; 0.1mol) in anhydrous dimethylformamide (20.0ml) and the
suspension was stirred at room temperature for 20mm. The mixture was treated, in
one portion, at room temperature, with a solution of 2-chloro-3-nitropyridine (147)
(15.9g; O.lmol) in anhydrous dimethylformamide (60.Oml) then stirred at 100°C (oil-
bath) with the exclusion of atmospheric moisture for 1 h.
The mixture was treated with water (30.0ml) and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (400m1) and
extracted with dichioromethane (3 x 250m1) to give the nitro compound (175)
178
(25.3g ;79%) which formed colourless crystals, nip. 137 - 139°C (from acetic acid),
u 1522 and 1355 (NO2) cm', ô (CDC13), 8.67 (1H, dd, J 1.7, 7.9 Hz, ArH), 8.38
(1H, dd, J 4.8, 1.7 Hz, AM), 8.19 - 8.05 (3H, m, ArFI) and 7.78 - 7.39 (4H, m, AM).
Found: C, 51.9; H, 2.6; N, 7.9%; m/z (El ms), 344, 346 (M).
cisllNQ requires: C, 52.2;H, 2.6;N, 8.1%;M344,346.
1-Bromo-2-(3-aminonvrid-2-vloxv)nanhthalefle (176)
A solution of the nitro compound (175) (13.8g ; 0.04 mol) in tetrahydrofuran
(400ml) was stirred and treated with a solution of stannous chloride dihydrate
(40.Og ; 0.2025 mol) in 2M hydrochloric acid (400ml) and the mixture was stirred
and heated under reflux for 1 h.
The cooled mixture was treated with 30% w/v aqueous sodium hydroxide solution
(1 60m1) and stirred at room temperature for 15 mm. then concentrated by rotary
evaporation and extracted with ether (3 x 250m1) to give the amine (176)
(1 1.2g ; 89%) which formed pale pink crystals m.p. 163 - 165°C (from acetic acid),
v 3445, 3300 and 3196 (NH) cm', 8H(CDC13) 8.19 - 8.15 (1H, m, ArH), 8.04 -
7.98 (2H, m, ArH), 7.74 - 7.55 (2H, m, ArH), 7.39 - 6.83 (4H, m, AM), and 5.38
(2H, s, NH2) (exch).
179
Found: C, 56.8; H, 3.5; N, 8.8%; m/z (El ms), 314,316 (M4).
jNZO requires : C, 57.1; H, 3.5; N, 8.9%; M 314, 316.
1-Bromo-2-(3-formamidopvrid-2-vloxv)naphthalefle (177)
A solution of the amine (176) (9.5g; 0.03mol) in 98 - 100% formic acid (60.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue treated with 10% w/v aqueous
sodium hydrogen carbonate (3 x 45.0ml) then extracted with dichloromethane (3 x
75.0 ml) to give the formamide (177) (8.4g ; 82%) which formed colourless crystals,
m.p. 147- 149°C (from ethanol), v 3372 (NB) and 1708 (C0) cm', 6H (CDC13)
Found; C, 55.6; H, 3.2; N, 8.0%; m/z (El ms) 342, 344 (NO,
_16% requires: C, 56.0; H, 3.2; N, 8.2%; M, 342, 344.
1-Bromo-2-(3-isocvanopvrid-2-vIoxv)naflhthalefle (178)
A solution of the formamide (177) (3.43g; 0.Olmol) in anhydrous dichloromethane
(50.0 ml) was stirred and treated in one portion with diisopropylethylamine (3.76g;
0.03mol) and the mixture was stirred and cooled to 0 - 5°C (ice - salt bath) then
treated dropwise with phosphoryl chloride (1.7g; 0.011 mol) and the mixture stirred
at room temperature for 4h.
180
The mixture was treated, dropwise, with 1M aqueous sodium carbonate solution
(50.0 ml) stirred at room temperature for lh then extracted with dichloromethane (2
x 25.0 ml) to give the isocyanide (178) (2.74g; 84%) which formed brown crystals,
m.p. 113 - 115 °C(from ethanol), v 2125 (NEC) cm' , oH [(CD3)2S0] 8.28- 8.04
(514, in, ArH), 7.77 - 7.56 (3H, in, ArH), and 7.31 - 7.25 (111, m, ArH)
Found; C, 58.6; H, 2.6; N, 8.3%; m/z (Ei ms) 324, 326
I6H9NrQ requires: C,59.1; H, 2.8; N, 8.6%; M, 324, 326.
The Attempted Aluminium Tribromide Catalysed Cydisation of
1-Bromo-2-(3-isocvanopvrid-2-vloxv)flaphthalefle (178)
A solution of the isocyanide (178) (0.65g) ; 0.002mol) in anhydrous dichioromethane
(10.Oml) was stirred under nitrogen and cooled to -78°C (solid CO 2 -acetone bath)
then treated dropwise with a solution of bromine (0.32g ; 0.002mol) in anhydrous
dichioromethane (10.0ml) and the mixture stirred at -78°C for 0.5h.
The mixture was treated with portions of a solution of aluminium tribromide (1.2g;
0.002mol) in anhydrous dichioromethane (10.Oml) then stirred under nitrogen and
heated under reflux for 4h.
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (32.0ml; 0.004mol)) and the mixture stirred at room
181
temperature for 1 5mm. The mixture was filtered to remove insoluble aluminium
residues, then extracted with dichloromethane (2 x 10.Oml) to give a brown gum
(0.34g) whose t.l.c. in hexane - ethyl acetate (7 : 3) over silica showed it to be a
complex mixture which was not further investigated.
1,3-Di-(2-nitrophenoxv)benzene (182)
A suspension of sodium hydride (4.4g ; 0.22mo1) in anhydrous dimethlyformaniide
(40.0m1) was stirred and treated at 0 - 10°C (ice-bath) with a solution of resorcinol
(181) (5.5g; 0.05mol) in anhydrous dimethylformamide (20.Oml). The suspension
was stirred at room temperature with the exclusion of atmospheric moisture for
1 5mm. then treated, in one portion, at room temperature, with a solution of
2-fluoronitrobenzene (68) (14.lg; 0.1mol) in anhydrous dimethylformamide (20.Oml)
and the mixture stirred and heated at 100°C (oil-bath) for lh.
The mixture was cooled, treated with water (30.0m1), and stirred at room temperature
for 15min then rotary evaporated. The residue was treated with water (200mi) and
extracted three times with dichloromethane (4 x 2000.Omi) to give the nitro
compound (182) (14.7g;84%), m.p. 84 - 86.5°C (lit34 88 - 890C), v 1542 and
1351 (NO2)cm'.
182
1g3Di-(2amjnophenox0benzene (183)
A solution of the nitro compound (182) (14.1g ; 0.06 mol) in dimethylformamide
(100m!) was hydrogenated over 10% palladium - on - charcoal (1.4g) at room
temperature and atmospheric pressure for 3.5h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
the amine (183) (11.6g ;99%), v 3465, 3368 and 3182 (NH2)cm' ,imp. 61-
64°C (lit 14 67 - 680C).
13-Di-(2-formamidophenoxv)benzene (184)
A solution of the amine (183) (1.5g ; 0.005mol) in 98 - 100% formic acid (20.0 ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue treated with 10% w/v aqueous
sodium hydrogen carbonate (3 x 10.Oml) and extracted with dichloromethane
(10.0 ml) to give a brown gum (1.9g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (1: 1) gave the formamide (184) (1.6g ; 92%)
which formed light brown crystals, m.p. 130 - 132.5°C (from ethanol - cyclohexane),
v 3269 (NH) and 1680 (C=O) cm', S (CDC13) 9.94 (2H, s, NH) (exch), 8.28 -
8.24 (211, m, CHO), 7.19 - 6.97 (8H, m, ArH), and 6.74 - 6.61 (4H, m, ArH).
183
Found; C, 68.1; H, 4.6; N, 7.6%; m/z (El ms), 348 (M').
c2L62Q!, requires; C, 69.0; H, 4.6; N, 8.0%; M 348.
1.3-Di-(2-isocyanophenoxv)benzene (185)
(a) A solution of the formamide (184) (1.4g ; 0.004mol) in anhydrous 1,2
dichloroethane (20.Oml) was stirred and treated with carbon tetrachloride (1.4g
0.0096mo1) then triphenylphosphine (2.6g ; 0.0096mo1)and the mixture stirred at
room temperature with the exclusion of atmospheric moisture for 15 mm.
Triethylamine (1.6g ; 0.016mol) was added and the mixture was stirred at 60°C (oil-
bath) for 2.5h.
The dark brown mixture was concentrated by rotary evaporation to remove the
dichioroethane giving a dark brown residue which was treated with water (10.Oml)
and extracted with dichioromethane (3 x 10.Oml) to give a brown gum (3.8g) whose
t.1.c. in hexane - ethyl acetate (3 2) over silica showed it to be a complex mixture
which did not contain the isocyanide (18 5) was not further investigated.
(b) A solution of the formamide (184) (6.9g ; 0.02) in anhydrous dichloromethane
(200 ml) was stirred and treated, in one portion, with diisopropylethylamine (15.2g;
0.12 mol). The mixture was cooled to 0 - 5°C (ice - salt bath) and treated dropwise
with phosphoryl chloride (6.8g ; 0.044 mol) then stirred at room temperature for 4h.
184
The pale yellow mixture was treated dropwise with 1M aqueous sodium carbonate
solution (200 ml) stirred at room temperature for I then extracted with
dichloromethane (200 ml) to give a brown oil (10.8g) which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) gave the isocyanide (185) (5.3g; 85%) as a
green oil v 2116 (NEC) cm'
Found: m/z (FAB ms) ; 313 (M1H).
HNQreuuires;_312.
The Attempted Cyclisation of 1,3-Di-(2-benzvloxvphenvl)isocvanidedibromide
(185).
A solution of the isocyanide (185) (0.63g ; 0.002mol) in anhydrous dichioromethane
(10.Oml) was stirred under nitrogen and cooled to - 78°C (solid CO2 - acetone bath),
then treated dropwise with a solution of bromine (0.35g ; 0.002 mol) in anhydrous
dichloromethane (10.0ml). The mixture was stirred at -78°C, under nitrogen for 0.5h
after which time t.l.c. indicated complete consumption of the starting material.
The mixture was stirred and treated with portions of a solution of aluminium
tribromide (2.2g; 0.008mol) in anhydrous dichloromethane (20.0ml) then heated
under reflux for 5h.
185
The suspension was allowed to cool then poured into 10% w/v aqueous sodium
hydrogen carbonate solution (62.Oml; 0.08mol)) and the mixture stirred at room
temperature for 1 5mm. The mixture was filtered to remove insoluble aluminium
residues, then extracted with dichloromethane (2 x 10.Oml) to give a brown gum
(I. I g) which was flash - chromatographed over silica, but gave no identifiable
material.
1 g7Di-(2-nitrophenoxv)naphthalene (189)
A suspension of sodium hydride (8.8g ; 0.44mol) in anhydrous dimethylformamide
(80.Oml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2,7-
dihydroxynapthalene (18 8) (16.Og ; 0.1mol) in anhydrous dimethylformamide
(40.Oml). The suspension was stirred at room temperature with the exclusion of
atmospheric moisture for 25 min then treated, in one portion, at room temperature,
with a solution of 2-fluoronitrobenzene (68) (28.2g; 0.2mol) in anhydrous
dimethylformamide (80.0ml) and the mixture was stirred and heated at 100°C (oil-
bath) for lh.
The mixture was treated with water (60.0ml), and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (400m1) and
extracted with ethyl acetate (4 x 300ml) to give the nitro compound (189)
(32.0g;80%), v 1523 and 1342 (NO2) cm', imp. 91 - 96°C (lit 34 107 - 110°C).
186
17-Di-(2-aminophenoxv)naphthalene (190)
A solution of the nitro compound (189) (16.1g ; 0.04 mol) in dimethylformaniide
(70.Oml) was hydrogenated over 10% palladium - on - charcoal (1.6g) at room
temperature and atmospheric pressure for 6.5h.
The mixture was filtered through celite and the filtrate was rotary evaporated to give
a yellow oil (10.3g) which was flash - chromatographed over silica.
Elution with hexane - ether (1: 1) gave the amine (190) (8.9g; 86%) as a yellow oil,
v 3445, 3325, and 3185 (NIH2) cm'.
A solution of the nitro compound (189) (10.1g ;0.025mo1) in tetrahydrofuran
(500m1) was stirred and treated with a solution of stannous chloride dihydrate (50.0g;
0.225mo1) in 2M aqueous hydrochloric acid (500m1) and the mixture stirred and
heated under reflux for lh.
The mixture was then treated with 30% w/v aqueous sodium hydroxide solution
(200m1) and stirred at room temperature for 15 mm. then concentrated by rotary
evaporation and extracted with ether (3 x SOOml) to give an orange - brown oil which
was flash - chromatographed over silica.
187
Elution with hexane - ethyl acetate (7 : 3) gave the amine (190) (7.1g; 83%) as a
colourless solid, v 3445, 3325, and 3185 (NH2) cm', m.p. 80 - 82°C, (lit 34 80 -
82°C).
17-Di-(2-formamidophenoxy)naphthalene (191)
A solution of the amine(190) (1.7g ; 0.005mol) in 98-100% formic acid (20.0ml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue was treated with 10% w/v
aqueous sodium hydrogen carbonate solution (3 x 10.Oml) and extracted with
dichioromethane (10.0ml) to give a pale brown sticky foam (1.5g) which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate gave a brown gum which solidified on standing to
give the formamide (191) (0.80g; 50%), m.p. 123 - 125°C, as light brown crystals
(from ethanol) v 3304 (NH) and 1686 (C=O) cm- 1 , & [(CD3)2S0] 10.0 (211, s,
NH) (exch), 8.32 - 8.27 (211, m, CHO), 7.99 - 7.71 (211, m, AM), and 7.26 - 6.98
(1211, m, AiR).
Found: C, 70.8; H, 4.5; N, 7.0%; m/z (FAB ms) , 399 (Mlfl
: C, 72.4; H, 4.5; N, 7.0%; M, 398.
188
(b) A solution of the amine (190) (0.68g; 0.002mol) in butyl formate (5.Oml) was
heated under reflux for 91h by which time t.1.c. indicated complete consumption of
the starting material.
Rotary evaporation of the solution gave a brown foam (0.75g) which was flash -
chromato graphed over silica.
Elution with hexane - ethyl acetate (1: 1) gave the formamide (191) (0.41g; 52%),
m.p. 117 - 120°C, as a pale brown solid, identified by comparison (m.p. and i.r.)
with an authentic sample prepared in (a) before.
1-Benzvloxv-2-nitrobenzene (200).
(a) A suspension of sodium hydride (8.8g ; 0.22mo1) in anhydrous dimethylformamide
(lOOm!) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2 -
nitrophenol (27.8g ; 0.2mol) in anhydrous dimethyfformamide (50.0ml) and the
suspension was then stirred at room temperature for 25mm. The mixture was treated,
in one portion, at room temperature, with a solution of benzyl bromide (199) (34.2g;
0.2mol) in anhydrous dimethoxyethane (10.Oml) and the mixture was then stirred at
room temperature for 1 7h.
The mixture was treated with water (1 0.Oml), and stirred at room temperature for
15min then rotary evaporated. The residue was treated with water (160m1) and
189
extracted with dichloromethane (3 x 200 ml) to give I -benzyloxy-2-nitrobenzene
(200) (45.3g; 99%) as an orange - red oil, v 1523 and 1351 (NO2) cm' identified
by comparison (i.r. and t.l.c in hexane ethyl acetate (7 : 3) over silica) with an
authentic sample 34.
(b) A suspension of sodium hydride (4.4g ; 0.11 mol) in anhydrous dimethoxyethane
(20.0ml) was stirred and treated at 0 - 10°C (ice-bath) with a solution of 2-
nitrophenol (1 3.9g ; 0. imol) in anhydrous dimethoxyethane (40.Oml) and the
suspension was then stirred at room temperature for 20mm. The mixture was treated,
in one portion, at room temperature, with a solution of benzyl bromide (199) (15.7g;
0. imol) in anhydrous dimethoxyethane (10.Oml) and the mixture was stirred and
heated at 100°C (oil-bath) for 6h.
The mixture was cooled, treated with water (10.Oml), and stirred at room temperature
for 15min then rotary evaporated. The residue was treated with water (80.Oml) and
extracted with dichioromethane (3 x 200 ml) to give a red oil which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (4: 1) gave the nitro compound (200) (20.7g;
90%) as a yellow - orange oil identified (i.r. spectrum and t.l.c.) with a sample
prepared in (a) above.
IP1I]
1-Amino-2-benzvloxvbenzene (201).
(a) A solution of the nitro compound (200) (9.2; 0.04mol) in tetrahydrofuran (400m1)
was treated with a solution of stannous chloride dlhydrate 40M g; 0.1 8mol) in 2M
aqueous hydrochloric acid (400m1) then stirred and heated under reflux for lb.
The mixture was treated with 30% w/v aqueous sodium hydroxide solution (320m1)
and stirred at room temperature for 15 mm, then rotary evaporated and extracted with
ether (3 x 500m1) to give the amine (201) as a red - brown oil (7.4g; 93%), v 3463,
3370 and 3194 (NH2) cm', identified by comparison [i.r. and t1c in hexane - ethyl
acetate (7 3) over silica] with an authentic sample 41.
N-0-Benzv1oxvnhenv0formamide (202).
(a) A solution of the amine (201) (0.99g; 0.005mol) in anhydrous toluene (20.Oml)
was stirred and treated with 98 - 100% formic acid (0.5m1; 0.01mol) and the
mixture was stirred and heated under reflux for 21h. Rotary evaporation of the
mixture gave a brown oil (0.97g) which was triturated with light petroleum - ether to
give the formamide (202) (0.54g; 47%), which was purified by bulb - to - bulb
distillation, b.p. 218°C! 0.5mmHg, m.p. 73 - 75 9C, Vm 3268 (NH), and 1661 (C=O)
cm', 8j (CDC13) 8.40 - 8.36 (111, m, CHO), 7.43 (111, s, NH) (exch), 7.41 - 7.38
(511, m, ArH), 7.06 - 6.94 (4H, m, ArH), and 6.98 (211, s, CH2).
191
Found: C, 73.6; H, 5.8; N, 6.1%; m/z (El ms), 227 (Md).
C, 74.0; H, 5.7; N, 6.2%; M, 227.
A solution of the amine (201) (0.99g; 0.005mol) in anhydrous xylene (20.0ml)
was stirred and treated with 98 - 100% formic acid (0.5m1; -0.0 imol) then the
mixture was stirred and heated under reflux for 19h.
The mixture was rotary evaporated to give a brown gum which was triturated with
light petroleum - ether to give the formamide (202) (0.63g; 56%), m.p. 69 - 71'C,
identified by comparison (imp. and i.r spectrum) with a sample obtained before.
A solution of the amine (201) (0.99g; 0.005mol) in ethyl formate (5.0ml) was
stirred and heated under reflux for 3h.
Rotary evaporation of the solution gave a brown oil (0.91g) which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (4: 1) gave the unreacted amine (201) (0.50g;
51%) identified by comparison [i.r. and t.l.c. in hexane ethyl acetate (7 : 3)over silica]
with an authentic sample prepared before.
192
Further elution with hexane - ethyl acetate (7 : 3) gave a brown oil (0.31g) which was
triturated with ether - light petroleum, to give the formamide (202) (0.20g; 15%)
which was purified by bulb - to - bulb distillation, b.p. 218°C/0.5mmllg, imp. 73 -
75°C, and was identified by comparison (imp. and i.r spectrum) with an authentic
sample prepared in (a) before.
A solution of the amine (201) (0.40g; 0.002mo1) in propyl formate (5.0ml) was
stirred and heated under reflux for 22h.
Rotary evaporation of the mixture gave a brown gum (0.33g) which was triturated
with light petroleum - ether to afford the formamide (202) (0.14g; 3 1%), m.p. 70 -
72°C, identified by comparison (m.p. and i.r spectrum) with a sample obtained in (a)
before.
A solution of the amine (201) (15.9g; 0.08mol) in butyl formate (80.0ml) was
stirred and heated under reflux for 24h. Rotary evaporation of the mixture gave a pale
brown residue which was triturated with light petroleum - ether to give the formamide
(202) (12.0g; 66%), m.p. 69 - 7 1°C, identified by comparison (m.p. and i.r spectrum)
with a sample obtained in (a) before.
A solution of the amine (201) (0.99g; 0.005mol) in anhydrous toluene (10.Oml)
was stirred and treated with formamide (0.22g; 0.2m1; 0.005mol) and the mixture was
193
stirred then heated under reflux for 3h. The mixture was rotary evaporated to give a
brown oil (1 .Og) whose t.1.c. in dichioromethane over silica showed it to be the
starting amine (201). The oil was treated with formamide (5.Oml) and the mixture was
heated under reflux for a further lh. Rotary evaporation gave a dark brown oil (4.1g)
which was treated with water (1 0.Oml) and extracted with dichioromethane (3 x
10.Oml) to give a brown oil (0.52g) which was dry flash - chromatographed over
silica.
Elution with hexane - dichloromethane (1: 4) gave the formamide (202) (0.27g;
25%), imp. 69 - 71 *C, identified by comparison (m.p. and i.r spectrum) with a sample
prepared in (a) before.
(g) A solution of the amine (201) (1.999; 0.Olmol) in anhydrous diethyl ether
(10.Oml) was stirred and treated dropwise at room temperature with freshly prepared
formic acetic anhydride (1 .5m1). The mixture was then stoppered and stirred at room
temperature for 24h.
Rotary evaporation of the mixture gave a brown gum (2.3g) which was flash -
chromatographed over silica.
194
Elution with hexane - ethyl acetate gave only intractable gums (total 1.9g) whose t.l.c.
in hexane - ethyl acetate showed them to be complex mixtures which were not further
investigated.
2-Benz'v1oxvDhenylisocvanide (203).
(a) A solution of the formamide (202) (4.5g ; 0.02mol) in anhydrous 1,2-
dichioroethane (lOOml) was stirred and treated with carbon tetrachloride (3.6g;
0.024mo1) followed by triphenylphosphine (6.5g ; 0.024mo1) and the mixture was
stirred at room temperature for 15 mm. Triethylamine (4.Og ; 0.04mol) was added
and the mixture was stirred at 60°C (oil-bath) for 2.5h.
The orange mixture was concentrated by rotary evaporation to give a brown residue
which was diluted with water (50.Oml) then extracted with dichloromethane (3 x
50.0ml) to give a pale brown residue (10.3g) which was flash - chromatographed over
silica.
Elution with hexane-ethyl acetate (7 : 3) gave a yellow oil which solidified on standing
to give the isocyanide (203) (2.4g; 61%), which formed light brown crystals m.p. 52 -
54°C (from ether), v 2123cm' ,6 (CDC13) 7.50 - 7.25 (7H, in, ArH), 7.01 - 6.89
(2H, m, Aril) and 5.19 (211, s, C112)
195
Found; C, 80.4; H, 5.3; N, 6.7%; m/z (El ms), 209 (Md)
cJthINO requires: C, 80.4; H, 5.3; N, 6.7%; M 209.
(b) A solution of the formaniide (202) (0.45g ; 0.002mol) in anhydrous
dichioromethane (20.0ml) was stirred and treated in one portion with
diisopropylethylamine (0.76g ; 0.006moI). The mixture was treated dropwise with
stirring at 0- 5 °C (ice-salt bath) with phosphoryl chloride (0.34g; 0.0022mo1) then
stirred at room temperature with the exclusion of atmospheric moisture for 4h.
The mixture was treated dropwise with 1M aqueous sodium carbonate solution
(10.Oml) and stirred at room temperature for I then diluted with water (10.Oml). and
extracted with dichloromethane (3 x 5.0 ml) to give a brown oil (0.35g) which was
flash - chromatographed over silica.
Elution with hexane - dichioromethane (1: 1) gave the isocyanide (203) as a brown
oil (0.09g), v2l35cm which was assumed to be the isocyanide (203).
Elution with hexane - ethyl acetate (7 : 3) gave the starting formamide (202) (0.20g;
50%), m.p. 70 - 72°C, identified by comparison (imp. and i.r spectrum) with an
authentic sample prepared before.
196
2Benzv1oxvphenvIisocVaflidedibrOmide (204)
A solution of the isocyanide (203) (0.42g ; 0.002mol) in anhydrous dichioromethane
(20.0ml) was stirred under nitrogen and cooled to -78°C (solid CO2 - acetone) then
treated dropwise with a solution of bromine (0.35g ; 0.002 mol) in anhydrous
dichioromethane (20.0ml). The mixture was stirred at -78°C under nitrogen for lh
after which time t.l.c. indicated complete consumption of the starting material. Rotary
evaporation of the mixture gave the isocyanide dibromide (204) (0.82g; 100%) as a
brown oil..
Found: m/z (El ms), 367 (Md).
CI3HnzNO requires : M, 367.
Found: m/z (El ins), 369 (M).
ci179Br81BrNO requires : M, 369.
Found: m/z (El ms), 371 (M4T).
C13H, 1 8 'Br2NO requires. M, 371.
The Attempted Aluminium Tribromide Catalysed Cyclisation of
2BenzvloxvnhenvlisoCvaflide (204)
A solution of the isocyanide (204) (0.42g ; 0.002mol) in anhydrous dichloromethane
(20.0ml) was stirred under nitrogen and cooled to -78°C (solid CO2 - acetone) then
197
treated dropwise with a solution of bromine (0.35g ; 0.002 mol) in anhydrous
dichioromethane (20.Oml). The mixture was stirred at -78°C under nitrogen for lb
after which time t.l.c. indicated complete consumption of the starting material. The
mixture was stirred under nitrogen and treated with portions of a solution of
aluminium tribromide (1.2g; 0.004mol) in anhydrous dichloromethane (10.0ml). The
mixture was then stirred at -78°C for 4h.
The orange - brown solution was allowed to warm to room temperature then poured
into 10% w/v aqueous sodium hydrogen carbonate solution (32.Oml; 0.04mol)) and
stirred at room temperature for 1 5mm. The mixture was filtered to remove insoluble
aluminium residues, then extracted with dichloromethane (2 x l0.Oml) to give a
brown oil (0.49g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) through to methanol gave only a series of
intractable solids and gums (total 0.39g) which were not further investigated.
The Attempted Zinc Chloride Catalysed Cyclisation of 2-Benzv1oxvphenvl
isocyanidedichloride (206)
A solution of the isocyanide (203) (0.42g ; 0.002mol) in anhydrous dichioromethane
(10.Omi) was stirred under nitrogen and cooled to -78°C (solid CO2 - acetone) then
treated dropwise with a solution of sulphuryl chloride (0.27g ; 0.002 mol) in
198
anhydrous dichioromethane (1O.Oml). The mixture was stirred at -78°C under
nitrogen for 2h after which time t.l.c. indicated complete consumption of the starting
material. The mixture was treated at room temperature with portions of a suspension
of zinc chloride (0.54g; 0.004mol) in anhydrous dichioromethane (10.0ml) and the
mixture was then stirred and heated under reflux with the exclusion of atmospheric
moisture for 22K
The brown solution was allowed to cool to room temperature then poured into 10%
w/v aqueous sodium hydrogen carbonate solution (32.0ml; 0.04mol)) and stirred at
room temperature for 1 5mm. The mixture was filtered to remove insoluble aluminium
residues, then extracted with dichioromethane (2 x 20.0m1) to give a brown oil
(0.49g) which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7 : 3) through to methanol gave only a series of
intractable gums (total 0.45g) which yielded no identifiable material.
2-BenzvloxvDhenvlisothiocvanate (208
A solution of the amine (201) (1.99g ; 0.0lmol) in glacial acetic acid (40.0mi) was
stirred and treated with a mixture of concentrated hydrochloric acid (10.Omi) and
water (10.0mi) then treated dropwise at room temperature with a solution of
199
thiophosgene (2.4g ; 0.02mol) in glacial acetic acid (5.0ml). The mixture was then
stirred at room temperature for 4h.
The mixture was diluted with water (50.0m1) then extracted with dichloromethane (3
x 100. Oml) and the combined dichioromethane extracts were washed with 10% w/v
aqueous sodium hydrogen carbonate solution (3 x 50.0ml) then rotary evaporated to
give a brown oil (3.1 g) which was flash - chromato graphed over silica.
Elution with hexane - dichloromethane (7 3) gave the isothiocyanate (208) (1.4g ;
58%) as a colourless oil, b.p. 212°C, 1.OmmHg, v 2058(N--C=S) cm', 6 (CDC13)
7.529 - 6.85 (911, in, ArH), and 5.17 (2H, s, C112)
Found; C, 68.7; H, 4.4; N, 5.7%; m/z (El ms), 241 (M4 ).
C14 NOS requires; C, 69.7; H, 4.6; N, 5.8%; M 241.
The Attempted Chlorination of 2-Benzv1oxyphenylisothiocyanate (208)
A solution of the isothiocyanate (208) (0.48g; 0.002mol) in anhydrous chloroform
was stirred and cooled to -10°C (ice - acetone bath) then saturated with a flow of
chlorine for 2h. The mixture was then stirred for a further 2h. Rotary evaporation
gave a yellow oil (0.62g) whose t1c in hexane - ethyl acetate (7 : 3) showed it to be a
complex mixture which was not further investigated.
200
The Attempted Aluminium Trichloride Catalysed Cyclisation of the
2-BenzvloxvphenvlisothiocVaflate (208).
A suspension of aluminium trichioride (lAg ; 0.008mol) in anhydrous
dichioromethane (40.Oml) was stirred under nitrogen and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of the isothiocyanate (208)
(0.96g ; 0.004mol) in anhydrous dichioromethane (20.0ml). The light brown
suspension was then stirred at room temperature for 4h.
The orange - brown suspension was poured into 10% w/v aqueous sodium hydrogen
carbonate (60.Oml) and stirred at room temperature for 15mm. then filtered to remove
insoluble aluminium residues, and extracted with dichloromethane (2 x 40.0ml) to
give an orange gum (0.46g) which was flash - chromatographed over silica.
Elution with hexane - dichloromethane (7 3 ) through to methanol gave only a series
of intractable gums (total 0.75g) which yielded no identifiable material.
2-Nitrobenzovl Chloride (211)
A slurry of 2-nitrobenzoic acid (210) (99.6g ; 0.6 mol) and thionyl chloride (91;
56.Oml ; 0.76 mol) was stirred and heated under reflux until the suspended solid
dissolved then for a further 20 mm. The excess thionyl chloride was distilled under
water pump vacuum and the residual oil was then distilled under oil pump vacuum to
give 2-nitrobenzoyl chloride (211) (79.3g ; 71 %), b.p. 106°C I 0.7mmhg, identified
by comparison (b.p. and t.l.c.) with an authentic sample.
201
N-Methyl, N-phenyl 2-nitrobenzamide (213)
A solution of N-methylaniline (212) (5.4g ; 0.05 mol) in glacial acetic acid (20.0ml)
was stirred and treated with fused sodium acetate (20.5g ; 0.25 mol) then the stirred
suspension was treated, dropwise, with a solution of 2-nitrobenzoylchloride (211)
(9.3g ; 0.05 mol) in glacial acetic acid (10.Oml). The resulting brown mixture was then
stirred at room temperature for 3h then rotary evaporated under high vacuum to give
a pale brown residue which was treated with water (15.0 ml), then made basic with 10
% w/v aqueous sodium hydrogen carbonate. The resulting suspension was filtered to
give the nitro compound (213) (7.8g; 61%) as a cream solid, m. p. 91 - 93°C (lit va1 48
94°C) u nia, 1680 (C = 0), 1520 and 1349 (NO2) CM-1 .
N-Methyl, N-phenyl 2-aminobenzamide (214)
(a) A solution of the nitro compound (213) (7.7g ; 0.03 mol) in tetrahydrofuran
(300ml) was stirred and treated with a solution of stannous chloride dihydrate (30g;
0.135 mol) in 2M hydrochloric acid (300ml) and the mixture was stirred and heated
under reflux for lh.
The mixture was treated with 30% w/v aqueous sodium hydroxide (240m1) and
stirred at room temperature for 15 mm. The mixture was then concentrated by rotary
evaporation and extracted with ether (3 x 900ml) to give the amine (214) (1.5g
22%)as a colourless solid, m.p. 123 - 125°C (lit. 48 124 - 1270C), uma,, 3464, 3368 and
3145 (NH) and 1685 (C = O) cm'.
202
(b)A solution of the nitro compound (213) (15.4g ; 0.06 mol) in ethanol (300m1) was
hydrogenated over 10% palladium - on - charcoal (1.54g) at room temperature and
atmospheric pressure for 2.0h. The mixture was filtered through ceite and the filtrate
was rotary evaporated to give the amine (214) (12.8g ; 95%) which formed
colourless crystals m.p. 124 - 126 1 C, uma, 3473, 3367 and 3144 (NH) and 1693 (C =
0) cm 1 , identical (m.p. and i.r spectrum) to a sample obtained in (a) before.
N-Methyl N-phenyl 2-formamidobenzamide (215)
(a) A solution of the amine (214) (2.26g; 0.Olmol) in 98-100% formic acid (20.Oml)
was stirred and heated under reflux for 3h.
The mixture was rotary evaporated and the residue was treated with 10% w/v
aqueous sodium hydrogen carbonate solution (25.Oml) then extracted with
dichioromethane (3 x 25.0ml) to give a sticky cream solid which was washed with 2M
aqueous hydrochloric acid and water and filtered to give a sticky cream solid (1.7g)
whose t.l.c. in hexane - ethyl acetate (1: 1) over silica showed it to be a complex
mixture which was not further investigated.
(b) A solution of the amine (214) (1.13g; 0.005mol) in ethyl formate (10.0ml) was
stirred and heated under refiux for lh. Rotary evaporation of the mixture
gvcunreacted starting material (214) (0.90g; 80%) m.p. 123.5 - 126°C identified by
comparison (m.p. and i.r) with an authentic sample.
203
(c) A solution of the amine (214) (7.9g; 0.035mo1) in butyl formate (87.5m1) was
stirred and heated under reflux for 72h by which time t.l.c. indicated no further change
in the composition of the reaction mixture.
Rotary evaporation of the mixture gave a pale brown solid which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (7; 3) gave starting material (214) (0.8g; 10%),
m.p. 125 - 126°C identified by comparison (m.p. and i.r. spectrum) with an authentic
sample.
Elution with hexane - ethyl acetate (7; 3) gave the formamide (215) (5.3g; 60%)
which formed colourless crystals, m.p. 97- 99°C (from cyclohexane), vma, 3159 (NH)
and 1692 (C=O)cm', 6H (CDC1 3) 8.44 - 8.30 (111, m, CHO), 7.24 (1H, s, NH)
(exch), 7.22 - 7.13 (5H, m, AM), 7.00 - 6.95 (411, m, ArH), and 3.50 (3H, s, C11 3).
Found; C, 70.2; H,5.5; N, 11.0% ;m/z(FABm5),255 (MIfl.
C,70.9; H,5.5; N, 10.8%; M, 254
(d) A solution of the amine (214) in propyl formate (5.Oml) was heated under reflux
for 30h by which time t1c. indicated no further change in the composition of the
reaction mixture.
204
Rotary evaporation of the mixture gave a colourless gum (0.34g) which was flash -
chromatographed over silica.
Elution with hexane - ethyl acetate (1: 1) gave a pale brown gum which was
triturated with ether to give the formamide (215) (0.17g; 33%), m.p. 91 - 93°C
identified by comparison (m.p., t.l.c and i.r spectrum) with an authentic sample.
prepared before.
(e) A solution of the amine (214) (2.3g, 0.01 mol) in anhydrous dichloromethane
(20.0ml) was stirred and treated dropwise at room temperature with freshly prepared
formic - acetic anhydride (1 . 5 ml) and the solution was then stirred for 24h at room
temperature. Rotary evaporation of the mixture gave a brown gum (3. ig) which was
flash chromatographed over silica, but gave no identifiable material.
N-Methyl N-phenyl 2-isocyanobenzamide (21€)
A solution of the formamide (215) (5. ig ; 0.02mol) in anhydrous dichioromethane
(lOOml) was stirred and treated, in one portion, with diisopropylethylamifle (7.8g;
0.06mol) then treated dropwise with stirring at 0 - 5°C (ice-salt bath) with phosphoryl
chloride (3.4g; 0.022mo1). The mixture was then stirred at room temperature with the
exclusion of atmospheric moisture for 4h.
205
The mixture was treated, dropwise, with 1M aqueous sodium carbonate solution
(lOOmI) then stirred at room temperature for lh. The mixture was diluted with water
(lOOmi) then extracted with dichioromethane (lOOmi) to give an orange - brown oil
which was flash - chromatographed over silica.
Elution with hexane - ethyl acetate (7: 3) gave a sticky brown solid (3.8g) which was
triturated with light petroleum - ether to give the isocyanide (216) (3.4g; 72%) which
formed pale yellow crystals, m.p. 86 - 87.5°C (from cyclohexane), Vm 2121 (NEC),
H (CDCI3) 7.28 - 7.13 (9H, m, ArH), and 3.52 (3H, s, CH 3)
Found: C, 76.1; H,5.2; N, 11.7%;m/z(FABms),237(MH 4).
C15I?NQJq1ires C,76.3; H,5. 1; N, 11.9%; M, 236.
N-Methyl, N-vhenyl 2isothiocvanatobeflZam1de (219)
A solution of the amine (214) (4.5g ; 0.02mol) in glacial acetic acid (lOOmi) was
stirred and treated with a mixture of concentrated hydrochloric acid (10.Oml) and
water (10.Oml) then treated dropwise at room temperature with a solution of
thiophosgene (4.6g; 0.04inol) in glacial acetic acid (10.0ml). The mixture was stirred
at room temperature for 4h.
The mixture was diluted with water (100m!) then extracted with dichioromethafle
(60.Oml) and the extract was then washed with 10 % w/v aqueous sodium hydrogen
206
carbonate and rotary evaporation to give a yellow oil which was triturated with light
petroleum 60 - 80 to give the isothiocyanate (219) (3.9g; 73%) which formed cream
crystals, m.p. 63 - 65°C (from cyclohexane), v 2020 (NC=S) cm 1 .
Found, C,66.8; H, 4.4; N, 10.4%; mlz (El ms) 268 (M),
C,67.2 ; H, 4.5 ; N, 10.5 % M, 268.
Attempted Brominatiofl Reactions of N-Methyl. N-phenyl 2-isocyano
benzamide (21
(a) A solution of the isocyanide (216) (0.47g ; 0.002mol) in anhydrous
dichloromethane (20.0ml) was stirred under nitrogen and cooled to -10°C (ice - salt
bath) then treated dropwise with a solution of bromine (0.35g ; 0.0022 mol) in
anhydrous dichloromethane (20.0ml). The mixture was stirred at -10°C for lh by
which time 0. c. indicated complete consumption of the starting material. Rotary
evaporation gave an orange foam (1.1 g) which was flash - chromatographed over
silica, but gave no identifiable material.
(b) Repetition of the reaction described in (a) before but at -78°C (solid CO2 -
acetone bath) gave an orange foam (0.81g) which was flash - chromatographed over
silica but gave no identifiable material.
207
The Attempted Chlorination of N-Methyl, N-phenyl 2-isocyano
benzamide(216).
A solution of the isocyanide (216) (0.47g ; 0.002mol) in anhydrous dichloromethane
(10.Oml) was stirred undr nitrogen and cooled to -78°C (solid CO 2 - acetone bath)
then was treated dropwise with a solution of suiphuryl chloride (0.27g ; 0.002 mol) in
anhydrous dichioromethane (10.Oml). The mixture was stirred at -78°C, under
nitrogen, for 1.5h after which time t.l.c. indicated complete consumption of the
starting material had been consumed. The mixture was rotary evaporated to give a
yellow foam (0.60g) which was flash - chromatographed over silica, but gave no
identifiable material.
The Attempted Aluminium Trichioride Catalysed Cyclisation of N-Methyl, N-
phenyl 2-isothiocyanatobenzamide (219)
(a) A suspension of aluminium trichioride (0.53g ; 0.004mol) in anhydrous
dichloromethane (20.Oml) was stirred under nitrogen and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of the isothiocyanate (219)
(0.54g ; 0.002mol) in anhydrous dichioromethane (10.Oml). The suspension was then
stirred at room temperature with the exclusion of atmospheric moisture for 4h.
The suspension was poured into 10% w/v aqueous sodium hydrogen carbonate
(30.Oml) and stirred at room temperature for 1 5mm. then filtered, to remove
insoluble aluminium residues and extracted with dichloromethane (3 x 20.0ml) to give
208
a yellow gum which on trituration with light petroleum 60- 80 and ether gave a
colourless solid (0.28g) which was flash chromatographed over silica but gave no
identifiable material.
(b) A suspension of aluminium trichloride (1.06g ; 0.008mol) in anhydrous
dichioromethane (40.0ml) was stirred under nitrogen,, and cooled to -10°C (ice -
acetone bath) then treated, dropwise, with a solution of the isothiocyanate (219)
(1.07g ; 0.004mol) in anhydrous dichioromethane (20.Oml). The suspension was then
stirred under reflux with the exclusion of atmospheric moisture for 4h.
The suspension was poured into 10% w/v aqueous sodium hydrogen carbonate
(60.Oml) and stirred at room temperature for 1 5mm, filtered to remove insoluble
aluminium residues, then extracted with dichloromethane (3 x 40.Oml) to give a
yellow oil which was wet flash - chromatographed over alumina, but gave no
identifiable material.
(c) A suspension of aluminium trichioride (0.53g ; 0.004mol) in anhydrous 1,2 -
dichloroethane (20.Oml) was stirred under nitrogen and cooled to -10°C (ice - acetone
bath) then treated, dropwise, with a solution of the isothiocyanate (219) (0.54g;
0.002mol) in anhydrous 1,2-dichloroethane (10.Oml). The suspension was then stirred
under reflux with the exclusion of atmospheric moisture for 4h.
209
The suspension was poured into 10% w/v aqueous sodium hydrogen carbonate
(30.Oml) and stirred at room temperature for 15mm. The mixture was filtered to
remove insoluble aluminium residues, then extracted with dichioromethane (3 x
20.Oml) to give a brown oil (0.47g) whose t.l.c. in hexane - ethyl acetate (1: 1) over
silica showed it to be starting material (219) and another product.
The brown oil was in 1,2 - dichioroethane and the above reaction was repeated under
reflux for 15h. This gave a brown oil (0.42g) which again was shown by t.1.c. in
hexane - ethyl acetate (1: 1) over silica to be starting material (219) and another
product. The oil was again recycled through the reaction as described before to give
a brown oil (0.31g) whose t.l.c in hexane - ethyl acetate (1: 1) over silica showed it
to be a complex mixture which was not further investigated.
The Attempted chlorination of the Isothiocyanate (219)
A solution of the isothiocyanate (219) (0.54g ; 0.002mol) in anhydrous chloroform
(20.0ml) was stirred and cooled to -10°C (ice - acetone bath) then treated with a flow
of chlorine gas for lh. The mixture was then stirred at -10°C for 0.5h.
Rotary evaporation gave a yellow foam (0.61g) which was triturated with light
petroleum - ether to give a yellow solid (0.61g) which was flash - chromatographed
over silica, but gave no identifiable material.
210
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